I was riding SPDs and had some knee pain. I went to a fitter (an old-school guy, Hans @ Bannings/EWB in Fullerton), and when I told him my right knee was hurting, the first thing he did was look at my cleats. He found that my right SPD cleat was misaligned by a few degrees, and that was enough. Once it was straight, my knee pain went away. The cleats on SPDs have to be properly aligned, or some users get knee pain.

In my case, I quit using SPDs and went with Speedplays, as they have much more float. Since then, no knee pain in more than 6,000 miles.