We depend pretty heavliy on the structure and type of elements used. Tables, id's, divs, etc. If you change something core the
JS code that builds the layout may break. It's hard to make a general statement or rule. The best way to do skin development is to alter a working skin/example. Trying to build one from scratch without internal knowledge with the layout code will be very hard. Just make small changes and test often and you'll have the best results. If you have a specfic problem/question please ask.