I've been using the same shoe/cleat combination (SPD) since I bought my bike last spring, and after several months have the bike fit pretty well dialed in. Lately I've been pushing myself more, riding longer distances, "attacking" hills (the quotes are to assure those who've read my posts that I still suck on hills, but not relative to how awful I was when I started out).
After a pretty strenuous ride early this week I experienced knee pain for the first time, just above the patella on my right knee. I was concerned, because I destroyed this knee 26 years ago in a climbing accident, and the patella is held together with wire to this day. I started checking everything, and when I changed clothes I noticed that the cleat in my right shoe was almost 1/2" further back toward the heel than in the left shoe. I moved it up even with the left shoe, and noticed at once that the ball of my foot was now right over the pedal.
Two hard rides since, and not a bit of knee pain. Lessons: at my age, any structural pain needs immediate attention; and the process of adjusting and fiddling with bike fit is never really over.