Simple's template system allows a great degree in design flexibility. Nevertheless, you must be aware of the Simple framework when creating a site design so that you aren't constantly fighting the system to get things working.
Your page will have at least two basic areas: the menu area and the content area. At a bare minimum, you'll need to provide two columns for these areas using either CSS or a table. Optionally, you can add "breadcrumbs" to your site, which are basically a set of links showing the visitor their location within the site.
Because Simple will be generating the breadcrumbs and the menu automatically (and because computers have no sense of design) you will want to impose limitations on those sections in the template to ensure that the system does not overstep its bounds.
Also, you'll need to consider whether you'd like to have templates for each section, or one template for the whole site. Having multiple templates ensures flexibility (and allows for sectional navigation), but it can be a lot of work to update the templates themselves. A singular template means losing a certain degree of flexibility, but it ensures the ability to quickly make a site-wide design change.
Lastly, make sure you give thought to your navigational model. Simple allows you to have a full-site menu (one that shows the entire site's tree structure unfolding), a sectional menu (where one page is designated the "root" of a section, and the menu displays the tree structure from there), or a local menu (where the menu only display's the current page's children). Using a sectional or local menu almost certainly means needing to have your own global navigation in the template which would need to be updated manually when a new 2nd level section is added, but it means less things on screen to confuse the visitor while he/she is browsing the site.