Whenever someone asks me about 'the best' frequent flyer program...I tell them to sign up for an airline from each of the three major alliances. For someone in the USA, they can't go wrong joining UA, AA, and DL or CO. Then, they are free to always choose the cheapest airfare from any of the legacy airlines and can always credit the mileage to one of the three alliances.
I'm sure other people can step up with some very different or more complex advice, but what I said above will best serve the fairly infrequent flyer based in the USA that wants to slowly rack up miles whenever they fly.
Also, the best program is different for everyone. One size doesn't fit all.