Theme help

I've been trying to get my head around exactly how I can prepare my own web page design using an external style sheet and adapt it for or fit it to, say for example, a zen sub theme. I get the impression that the main concern is that one builds one's page to suit a 1. 2. 3 or even 4 column design with header and footer and then depending on one's basic theme one can add blocks for content within those column areas and designate which content goes in which block? Perhaps I just haven't messed around enough yet with the other themes.