If I was building the site from scratch I would build it in such a way to minimize markup as CSS. I would probably do minimal Photoshop mockups and iterate rapidly in HTML/CSS, and the design would be very much driven by efficiency of the markup and CSS.
However in our case we had a graphic designer who had never done anything on the web before. This may seem like an insane way to design a web product, but the result is that we ended up with a brand that was entirely unique on the web, and this gave us a real tangible benefit when it came to attracting our initial userbase and business partnerships.
In the end the same functionality could have been built and reasonably well styled with 1000 lines of CSS, but we purposefully chose to go the longer route for branding purposes.