I thoroughly enjoy using this program to draw my artwork of cartoon characters. Clean and easy with the layers and line tool. I just have one suggestion that hopefully wouldn't be too hard to implement, and would make working with the linework even cleaner.
In the program Paint Tool Sai, there's a checkbox for each layer that says "Preserve Opacity," so that when the user draws on the layer, the alpha values are not changed, but the RGB values are. This really helps when you want to go back and color over the linework to have colored lines, instead of the standard black. It's impossible to do this, however, in Paint.NET with anti-aliasing on (which helps to make the lines look far cleaner than without it), since the anti-aliased pixels are all a different opacity, and using the fill or brush tool over them changes the opacity as well. Due to that, I always have to turn anti-aliasing off to do the colored linework on my art. If Paint.NET had the Preserve-Opacity feature, I could leave anti-aliasing on, as well as still being able to do colored linework. Hope it's not that hard of an implementation...