The game getting the most play by my local gaming group has been Sentinels of the Multiverse.
It is a cooperative card game, where each player takes on the role of a super hero, and as a team battles against a villain in various exotic locales.
Each player selects a hero, represented by a deck of cards unique to that hero. The cards represent the various powers, actions, abilities, equipment, etc., for the hero. The players then select a villain to play against (represented by a deck as well), and an environment to play at (again, with its own deck). The decks are fixed; that is, it is not a deck building game or customizable card game. Victory typically is achieved by getting the villain down to 0 hit points, although some villains may have unique victory conditions.
The heroes, villains, and environments all play very differently from one another. You could play with the same heroes and keep changing the villains and/or environments, and have a completely different feel to each game, requiring different tactics each time through. There are also a lot of synergies that can be found between the different heroes, and you have the best chance for success when you look for these and work as a team. This aspect of the game does mean difficulty can swing wildly from one game to the next depending on the heroes, villain, and environment chosen. However, each hero and villain does have a difficulty rating that serves as a pretty good general guide. Furthermore, each villain has Advanced difficulty rules that can be used to make a villain harder if you find he/she/it is too easy.
Theme-wise, the game hits it spot-on. To me it actually has a CoH vibe to it; all original heroes that capture a lot of the archetypes of the genre while still having a setting and background that is their own. Each card has a quote on it from a "comic," with the comics issue number and name, which is a nice little touch to help set the theme of the game.
The flow of the game is: Villain Turn, a turn for each hero, and then environment turn. The villain turn involves playing a card from the villain deck and resolving all actions on villain cards in play. During each hero's turn, the player can play a card and use a power (every hero has one default power, and then may get more by playing cards). Finally, environments provide a wide variety of effects, not all negative - some may include police backup, or have equal chance of attacking villain targets.
Games play relatively quickly (usually under an hour), so in a single evening its possibly to try a wide variety of match-ups. The game is designed for 2 - 5 players, and has a built in mechanic to help it scale. It been my local groups go-to game for most nice, since it is quick and easy to setup, provides lots of tactical options, lots of variety, and is just plain fun.