You really should familiarize yourself with each credit card program and then overlay it over your spending patterns and priorities to determine what the best card is for you.
First, analyze your spending patterns to see WHERE you're spending your money. If the great majority of your spending is on hotels and dining out, you should investigate which cards offer the best accumulation rate in those two categories. Most hotel branded credit cards offer very nice bonuses for charging hotel stays on their card. If they offer double miles on dining out, then that's even better. Because, obviously, the quicker you can accumulate points, the better.
Secondly, determine ahead of time how you'd like to redeem your points. If you want to save for a great vacation, it'd be nice to realize in the beginning that Marriott has a much bigger presence in the Caribbean than Starwood. Or that Hilton doesn't have any hotels on Maui.
Finally, go to Flyertalk and stay abreast on lucrative signing bonuses. There have been some very nice signing bonuses in the last few months from CapOne, Chase and Citibank.
I signed up for a CapOne Venture card during their promo last year where they matched your airline mile account, up to 100,000, if you spent $1000 spend in the first 3 months. I pocketed 110,000 CapOne miles, worth $1100 -- and the annual fee was waived. And the $1100 wasn't a fuzzy number because it's cash back. Plus it earns double miles on everything. Just putting one daughter's tuition on the card earns us 50,000 C/O miles per year. That's $500 towards our next vacation.
I have to say that I love the freedom of booking any airline and any hotel and getting paid back in cash. No more searching high and low for award flights for four. No more booking crappy itineraries just because it was a low tier award flight. I just pick where I want to go, when I want to go, and get reimbursed in cash. Plus, I still accumulate the miles/points on the airline and hotel I choose.