I have been working in BBEdit a lot lately, with 20+ documents open at a time. I have found that after several hours of editing, BBEdit would become sluggish. Just about anything I would try to do (find and replace, cut and paste, even just typing) would be met by a a roughly one-second delay before the action would take place.
One of many ways in which BBEdit Doesn't SuckĀ® is that it has a remarkably long undo history. If you've got 20+ documents undergoing heavy editing, by the end of the day, that undo history is getting a little weighty (computationally speaking).
The Fix: Select 'Clear Undo History' from the Edit menu. Presto, no more slowdowns...
robg adds: As indicated in the comments below, the above fix actually won't work; quitting and restarting BBEdit is the only known cure at present. I'm leaving this 'un-hint' up, however, for those who may be searching for an answer to the problem. As you can read in the comments, according to the folks at BBEdit, the slowdown is due to an OS X 10.4 bug, which they've reported to Apple -- so hopefully it will be fixed in a future system update. For now, though, you'll have to quit/relaunch BBEdit if this happens to you...]