Ah, the quest for the perfect back. I have two Timbuk2 bags (medium and small) and a North Face backpack. To be honest, my North Face backpack is the most comfortable when I ride, especially if I have to carry more stuff. I have some back issues, so it's better for me to have all the weight evenly distributed across my back. I am a petite woman and have found that the medium-sized Timbuk2 bag is just too heavy for me (I tend to put more in it). The small size works well, but not if I have to carry more things.

I guess a lot of this is personal preference, but I would recommend that if you're having trouble, try a good, old-fashioned backpack (i.e., one made for day hikes).

This might be against the grain, but I have been using a Novara Buzz messenger bag for quite a while now and it is still in use for my commutes. It has lasted me through college, two years of nursing school, countless clinical rotations (constantly being opened and closed and thrown around for a quick grab for a drug book or something), etc. It had some HEAVY books in it all the time but still shows very little signs of wear. I now commute to a hospital five days a week and it still holds up extremely well.

I used a large size TimBuk2 bag for a while, but like a prior poster had stated, but ended up not liking it because of the unstable and unmanageable feeling I would get whenever I was in the drops. It is great for hauling groceries when I riding my beach cruiser, but aside from that it doesn't get used.

Another vote for Chrome Metropolis
 

It's waterproof, holds all my work clothes, lunch and has room for a few extra's. I max it out from time to time, but it's so heavy at that point that I feel I've maxed out the single-shoulder strap concept at that point. So if you need more capacity than Metropolis, I'd recommend a two-shoulder solution like the Kremlin.

Nice extra's are the flasher tab, buckle for taking up the slack of extra strap and the ability to do everything one-handed. More on my blog...