I am one of the worst artists here. But here is how I do it.
I use photoshop (Version 5.5). Photoshop allows you to select both the size AND dpi of your image. I generally work at actual size, at either 300 or 150 dpi. Plan on having a lot of ram if you want to work at 300 dpi on marquee/overlay/sideart size images.
I use layers. Lots and lots of them. Generally each and every item on the artwork is a layer. That allows you to easily change and edit anything you want.
This is the last thing I did. This is not an original piece. This is a standard Assault overlay. I spent a long time fixing it up, when I downloaded it, it was pieced together from multiple scans, but now it is ready to print.