Each of the big programs has its strengths and weaknesses. Each has a different type of marquee award and a different "ideal" earning scenario. Your paid stay pattern and reward type desires will likely lead you to a natural answer.

Paid stay pattern includes everything - brand/service level, whether your corp rate includes breakfast, your frequent locations, whether you tend to do 1-nighters or weeklong stays, whether you tend to stay at urban hotels or resorts, use of extended-stay brands, and other factors.

With lots of non-stay paths to elite status and points in some programs, you may also choose a backup program. I stay fairly active in at least 3 programs (sometimes 4) in order to maximize coverage when it's time to redeem awards.