Could perhaps be swap files getting overly large. Does it get really slow? Try starting Activity Monitor (in Applications/Utilities, IIRC), and look at the memory tab. If the VM size is more than a 'few' dozen GB, then this might be the culprit. If any individual app is showing huge amounts of Virtual Memory, then it's a problem with that app.
see
Mac OS X: Reading system memory usage in Activity Monitor for a brief intro. As Apple say, don't worry about the amout of 'free' memory.