Lots of great comments already.
I spent 2000-2003 flying out of Denver 25-40 weeks/yr. A lot of this will become routine. As others mentioned, pick your brands airline/hotel/car and stick with them as much as possible.
When I was in Denver, the company I worked for during the first 2 1/2 years made me pick the cheapest flights regardless of carrier. And we had a travel coordinator who booked our hotel rooms (usually as cheap as possible). The last 1 1/2 years, I had some leeway in choosing my own flights and hotels. That was better.
The big question I have for you is, will you be going to different / random places every week, or will it be the same places over and over?
During my time in Denver, I went to random places every week (26 states in 4 years). During the past decade, I've been primarily traveling to the same locations - SF Bay Area, Singapore, Bangalore, Boston, Austin, etc.
The kids have left home now so I went back on the road a few months ago. Since May, I've been to Spain, India, Florida, Melbourne (Australia) and I've got a few more Asia destinations coming up. I'm kind of getting too old for this stuff but, hey, it's a job. And I always enjoy going someplace new.
The main thing to remember - as you explain to friends and family - when you're traveling for work, you don't get to pick the destination. Sometimes it's South Beach Miami, other times it's Terre Haute, Indiana.