Well, think of what you want to get in terms of your travel rewards card. For instance, if you want to get elite status, the Delta Platinum Amex (yearly fee of $75) gives you: 5k MQM upon your first purchase, another 10k MQM at the $25k spending level, and a final 10k MQM when you hit the $50k spending level. That, in and of itself, is silver status. If you get an AA credit card (I'm not very familiar with their ff plan), I believe every mile you accrue with them counts towards your million miler status (going towards lifetime status).
That being said, mile cards are probably not worth it. There's been recent devaluations in most FF plans and if you don't have status (at least on Delta), you might find it difficult to get reasonable flight fares for your points. I used my Delta Plat to hit the MQM levels to help get me to platinum status faster this year, but once I hit that threshold, I started going to my Amex enrolled in Membership Rewards. Those points can be transferred to a lot of airlines. There are some Gold and Platinum Amex signup bonuses lately ranging from 15k to 50k MR points, but some of those are rather targeted and require RSVP codes.
The Starwood gives you some of the best point transfers available and is a favorite among a lot of frequent fliers. At the same time, I believe they've just started to charge a yearly fee. That being said, there are often specials where if you transfer say 20k hotel points to 20k Delta bonus miles, you get a certain percentage bonus added on. Oh, and it helps that they have some swank hotels there too...
If you stay at Hiltons, the Hilton Platinum Amex is free and offers up to 5 points per dollar spent. I charged a good amount on it last year and while the points aren't worth it in small quantities, they become worth it when you hit higher point thresholds. At 175k, you get 6 nights free at any category 6 (their highest, but doesn't include their Waldorf Astoria collection).
Anyway, it's really dependent on what airline you fly, what you're trying to get from your program, and where you want to stay. If none of those really matter to you, then you shouldn't try to lock yourself into any one program unless they offer very flexible transfers (such as Starwood or MR). For the average person, however, cash back would probably work better in terms of tangible results, especially since the nicer rewards for a lot of these cards aren't available until you reach a very very high spending threshold...
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