Setting up your design
Just about any design in the world can be turned into a WordPress theme. However, there are some general guidelines you can follow—both in the design and the HTML/CSS build of your theme—which will easily convert the design into a theme.
Designing your theme to be WordPress friendly
While you can design your blog any way that you want, a good way to start would be with one of the standard blog layouts.
Note that while these different standard layouts have differing numbers of columns and column widths, they all have these essential parts:
Header
Main column
Side column(s)
Footer
WordPress expects your theme to follow this pattern, and so it provides functions that make it easier to create a theme that has this pattern. As you're designing your first blog theme, I suggest including these parts. Also, a design that stays within the same general design patterns of WordPress themes will most easily accommodate existing plugins and widgets.
That being said, a common situation in...