Pretty much anything not MSPaint has layers these days, so you won't have a problem there.
If you're looking for something free, MyPaint is decent, but from experience has poor compatibility with Monoprice tablets, which you may end up getting. Someone else can confirm this, it's been a while.
SAI seems to be the standard for a lot of people. It's some $50-60, which is a pretty good price compared to some other software.