A new Mass Effect game is currently in production. Not much is known about it, beyond the few intriguing snippets that can be extrapolated from the teaser. Where Mass Effect: Andromeda attempted to be an independent game set in the same universe, this new entry appears to be interested in building on the original trilogy.
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This is evidenced by the teaser's use of audio referencing the original trilogy's timeline and the appearance of a derelict mass relay. This impression is further reinforced by the appearance of Liara T'soni, a major character from the games, uncovering the remains of Shepard's armor. While the new storyline has not been revealed, the original trilogy did leave a number of unanswered questions and loose ends that could be explored in the new game.
9 Leviathan
Mass Effect 3's Leviathan DLC followed the search for the titular entity, which turned out to be the Reapers' original creator. They are persuaded to join Shepard, but state this is only for their survival. There is still a lot about them that is unknown.
Their dialogue with Shepard hints at plans for after the war ends. Revisiting Leviathan could be a great opportunity to explore their history and motivations in more detail. Given their superiority complex, Leviathan could even return as a new antagonist, allowing for an enemy that somewhat resembles the Reapers while also being something new and different.
8 Krogan Post-Reapers
Every Mass Effect player knows of the genophage, the plague designed to keep the Krogan population from exploding, which is finally cured in Mass Effect 3 (assuming Shepard chooses not to sabotage it). While the game hints at different outcomes depending on whether Eve survives, eradicating the genophage is going to cause some massive changes to Tuchanka.
While Eve may try to rein in the Krogans' violent impulses, they are still a naturally aggressive race with a long history of warmongering. Many of the Krogan will not be keen to live in peace. In Mass Effect 3, there was a desire among the Krogan to take revenge for the genophage. At best, this will lead to internal conflict and possibly civil war on Tuchanka, at worst it means a second Krogan rebellion against the rest of the galaxy. Either way, there are serious repercussions that could call into question not only the ethics of the genophage but also its cure.
7 Lost Civilizations
The ancient Prothean race was crucial to the original trilogy, but they were not the first intelligent race in the galaxy. Thousands of civilizations were wiped out by the Reapers long before the Protheans. While they may be the most recent and therefore best preserved, who is to say there are no other ruins or artifacts leftover from older cycles?
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The original trilogy offered hints in the form of possible descendants such as the Keepers and the "adjutant" enemy. But even these still leave many unanswered questions. Such discoveries would be an incredible find, certainly exciting an archeologist like Liara T'soni.
6 Shepard's Legacy
Shepard's legacy would depend on which ending the player chose at the end of Mass Effect 3, where they could either destroy the Reapers but die in the process, or take control of the Reapers and turn them into a force for good. The latter option could offer some interesting opportunities, as it means Shepard could still be alive (albeit uploaded into a computer network), and the Reapers suddenly on the player's side.
If the former ending is assumed, there would still be room to explore the way Shepard inspired others. The teaser showed Liara recovering Shepard's armor, implying that their legacy will be explored to some degree regardless of which ending is chosen.
The Mass Effect series introduced players to a variety of formidable species. They became acquainted with the Asari, Quarians, Krogan, and Turians. Other species, such as the Vorcha, Elcor, Hanar, Batarians, and the deceptively mighty Volus, didn't get much of the spotlight.
The new game could expand on these races, perhaps by giving the player an opportunity to visit their homeworld. Perhaps it could introduce some of them as squad members. It would an opportunity to subvert some of the stereotypes, such as creating a more sympathetic Batarian or Vorcha, but it could also be used as a way of adding new gameplay options.
5 Reclaiming Rannoch
The fascinating tech experts known as Quarians became an iconic race thanks to fan-favorite party member Tali. They were driven from their homeworld of Rannoch by their own creations, the Geth.
In Mass Effect 3, Shepard is dragged into a poorly organized campaign to take back Rannoch, the outcome of which is determined by the player. Assuming the Quarians succeed, there are inevitable challenges that will come with resettling the planet. They would have trouble breathing their own atmosphere due to their fragile immune systems, for instance. It would be fascinating to see how the race adapted to life back on their former planet.
4 Keepers
The strange insect-like species known as the "Keepers" appeared throughout the original trilogy, but not much about them is actually known beyond the fact that they are directly linked to the Citadel. Some theories are proposed in the games, but none of them are ever explicitly confirmed or denied.
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Assuming the Keepers are still maintaining the Citadel by the time the new game takes place, it would be interesting to learn more about how they work. There is also the broader question of where exactly they came from. Were they once an intelligent civilization that was wiped out by the Reapers? If the Citadel is revisited there may be a good opportunity to finally get some answers.
3 Prothean History and Culture
While they had a major impact on the original trilogy, information on the Prothean Civilization was limited. Fans know more about their technology than their actual history as a species. Mast Effect 3's DLC From Ashes offered a bit more insight thanks to Javvik, but even this was focused more on the Prothean Empire at the time of the Reapers' Invasion (with very little on the 50,000 years prior).
Without the pressure of stopping the Reapers, it could be an opportunity to explore the Protheans in more detail, perhaps offering a glimpse into their history, some notable members of the species and what their civilization was like in its prime. Between Javvik's first-hand knowledge and Liara's extensive research, there must be a way to make this happen.
2 The Fate Of Shepard's Friends
Liara's presence in the trailer indicates that long-term fans will reconnect with at least one old friend, but Shepard had numerous allies over the course of the trilogy. It has been theorized from a trailer of the next-gen Mass Effect adventure that the new game takes place a few centuries later, meaning most of Shepard's friends will have died by this point.
However, this does not rule out learning what happened to Shepard's crew after the Reaper invasion. Assuming said theory is wrong, then there would certainly be room for not only reuniting with old friends but also exploring how they have grown between games. Although it would make sense to focus on new characters, there is definitely potential for the post-Reaper stories of Tali or Garrus.
1 Humanity's Place in the Galaxy
The original Mass Effect put a lot of focus on tension between humanity and other races. Humanity was new to the alliance and widely distrusted by other species. That changed when humanity gained a seat on the council and took a more prominent role in interstellar politics.
While humanity may have earned a better overall standing in the galaxy, this theme continued with the rise of the pro-human group Cerberus and Udina trying to oust the other council members. As this was such a prominent theme in the original trilogy, it would make sense for the new game to further explore humanity's influence and status.