Sounds like a pretty common problem for a lot of us whether it's 5000 or 500,000 cards. I don't know what the "best" way to do it is, but what I am going to try and do is keep them all sorted by make, year, and sets first. Complete sets won't be messed with except for as a set and any small partial sets would be available for trading or selling or whatever. My player collections will be separated from those after the base card for that set was included in the set. So basically a set collection, followed by player collection, and then trade or sell collection.
Now if anyone would like to come do this for me....
~ T-Bone ~
My ex-wife hated this hobby which only made me like it more!