Mass Effect 3 will mark the end of Commander Shepard's story. It won't be the end of the series, though. BioWare plans to make additional ME games and they're looking back at the series lore for inspiration.
"Without going down any specific path, you can think of many, many different areas throughout the IP, throughout the history, where there are large wars to be won, large battles to be had, and a lot of development to be done around where these races came from, how they came about," executive producer Chris Gamble told OXM UK. "We have so much to draw from."
At the start of the Mass Effect series, humanity had only been on the galactic stage for a matter of decades. Even in that short period of time, though, there's a bunch of material to work with. For example, mankind fought the Turians in the "First Contact War" about 25 years prior to ME1.
Throughout the games, you also learn about other larger conflicts that occurred before humanity began interstellar travel. The galaxy was almost overrun by insects known as the rachni. The warlike race that defeated them, the krogan, then attempted to conquer all civilized space. There's also the matter of the geth, the advanced robots that became self-aware and turned on their quarian masters. All of these events could be shaped into games.
However, it's tough to top the Reapers. The Reapers, central antagonists of the ME trilogy, are a mysterious army that wipes out all organic life in the galaxy every few millenia before going back into hibernation in "dark space." This cycle of total annihilation and rebirth presents easy opportunities for new games because it gives BioWare a blank slate to work with. The next Mass Effect trilogy could star, say, the Protheans or some other forgotten race that tried to stop the Reapers and failed.
It will be easier to speculate on Mass Effect's future after ME3 has been released. If BioWare is already plotting their next move, that game will likely contain hints about the series' new direction. Look for the game to hit stores in March.