They have to keep the different domination note apart themselves by either folding the note a certain way or keeping it in a different place if they take them out with them.
If they are given them in change then they have to trust the cashier and store the notes according to their folding/placement plan..
The American government has been discussing plans to make it easier to years (maybe even decades!)
The US has dragged its feet for decades over this issue. The excuse is that the public wouldn't understand, and would be totally confused if new designs of notes were issued, whether by size (like the UK), or by embossing (like the Euro). Are the people of the US really that thick? Of course, there's the ''cost to industry'' for the changes that would be needed to those macines that take and issue notes. Well, they did it in Europe without too much trouble.