Reviving a dated topic because I stumbled across this thread looking for the exact same thing.
First things first: Planescape = best RPG ever.
After 14 years (that I by no means spent avoiding playing other RPGs) it still stands out as the single best experience. It might be tough for new gamers to pick up now, since the graphics are old and people sort of expect voice acting these days. But for anyone not scared of older games, play it if you have not done so already.
Baldur's Gate. Another of the great ones. And recently re-launched for iPads. Where the outdated graphics seems much more acceptable. So if you want to play one of the RPG genre-definers, and have an iPad, give it a shot there rather than go through the terror of 2D graphics on your PC.
Dragon Age comes in as a close 2nd. It is one of the few RPGs I played multiple times. Simply because I started over after buying the ultimate edition (lost the original CD - the only game I ever bought twice). Great character development options, both roleplaying wise, but also skills, class and gear. Good for hours of gameplay. Also one of the few more recent games where most classes can be played equally because you can tweak your companions to fill any role, and control them 100%.
Special mention to Dragon Age 2. It is a completely different game than Dragon Age: Origins. But interesting for you for the simple fact that it is a lot closer to Mass Effect 2 in gameplay. So if you are looking for a Mass Effect replacement, DA2 should be your go-to game.
Other options for story-driven games are Final Fantasy. However, most of them require Playstations to play, and many of them only work on PS2 (PS3 cannot play legacy games - or at least not the new models). FF games have always been very story-driven, although they do follow a rather well defined red thread and there are very few options for roleplaying. Consider them more like playing through a good book, you cannot change the course of events, but you get to feel part of the progression. They do not allow character generation, but the characters are often so well made that it makes no difference. And most of them allow you to specialize each group member whichever way you want and set your team as you want. So having female "sidekicks" is almost the same as having a female main character.
You could also look into Neverwinter Night. Since they allow for co-op playing through the singleplayer campaign. It is a bit like playing an MMO, but without the grinds since you get to progress the story after each quest.
