Ascension: Rise of Vigil (RoV), released in 2013, is the fifth Ascension set, and functions as a stand-alone game (2-4 players) or in combination with any other set. The next set released, Ascension: Darkness Unleashed (DU), is specifically designed to go with RoV, and these sets work exceptionally well together, including when mixed with other sets.
RoV adds the new mechanic of 'energy shards'. When these cards appear in the center row, another card is immediately played on top of them, and they are acquired for free when you acquire the card they are under. They are added to your deck and also play 'for free' -- you immediately draw to replace. They are then used to 'power up' other cards; if you have three energy shards, you may power up all cards requiring either 1, 2, or 3 energy. This takes a playthrough or two to get used to, but once you learn it, it is a fun and engaging mechanic.
The game makers knew full well that this was going to be combined with other sets, so the cards hit hard on the new mechanic -- the better to avoid becoming diluted. They also learned well the lesson that players like Big Powerful Cards, and introduced the first ever nine-cost hero (Oziah, Judge of Logos; Enlightened); DU then introduced the first nine-powered monster (discounting promo cards).
RoV and DU may be bought together in the Ascension Year Three Collector's Edition, which is an excellent deal, aside from one thing; when the games are sold separately they contain extra energy shards for when they are combined with other sets; in the Year Three box, it is assumed that they are combining with each other, and no additional cards are provided; this has a negative impact on game play if you do combine them with other sets.
This error aside the energy shards are an excellent new mechanic. This is approximately the point at which it become infeasible to play using all released sets, and this problem has increased since then. I personally like playing with the first four expansions as one set, and then starting a new set around RoV/DU, but they play well with any other 2-3 sets.