I have 50k uniques daily with a single line text-ads space.
What would you do? Would you sell your own ads?
I would hire an ad agency and sign an exclusive deal with them to broker everything out. If you can't find one, or need help choosing one, don't do the exclusive deal, and just juggle their ads and see which few networks do the best. Never rely on one agency unless they have paid you in the past.
If your site has a lot of uniques, hiring an ad agency will give you access to some large volume advertisers that you normally wouldn't have access to via an affiliate network. You're going to have to do some research, but I had already recommended AvenueA.com as an ad agency to Nitroy2k because they used to represent a site of my friend. He was able to sell advertising for some insane rate of like $15 CPM with four or five slots on each page for different advertisers. But again, he was pushing some serious traffic, and the only reason he stopped using them was because he was able to hire his own ad sales team and keep track of all of the sales and accounting on his own. I don't know if 50k uniques a day will qualify for them, but it doesn't hurt to try. If they don't accept you, there are tons of other ones around, just check the Business.com directory for interactive ad agencies. Best of luck.