I would pick a card from an airline that operates your local hub.
For most of the airline cards, those with an annual fee of under $100 will only offer about 1 mile per dollar spent. Those over $100/year will typically offer more like 2 miles per dollar spent. Obviously, if you use the card to book on a specific airline, you earn more miles.
My closest international gateway is IAD, one of UAL's hubs, so I have UAL rewards card. What is also cool about United and US Airways is that you can use miles on other Star Alliance Partner Airlines. Delta is a member of the SkyTeam Alliance (strong connections with Air France/KLM/Korean/Alitalia); American is a member of the One-World Alliance (strong connection with British Airways/JAL/Qantas).
Since I use my UAL card for everything, even for items costing less than $1.00 like bubble gum, I generally earn well over 30K miles a year from credit card use. It takes about 50K miles to book my most-traveled route from IAD to FRA/MUC, so I get a "free" round-trip to Europe about every 18 months or so. Consider that such tickets are worth around $1K or more, I see this personally as being more valuable than a cash rewards card alone.
Of course, there are blackout dates. Finding seats in the summer months or around Christmas can be difficult. But I have found that traveling to places outside of these high-traffic times of the year can be more rewarding anyway.