I think there are a variety of things to look at during the mockup phase - what works for one site may not work for another.
It's important to identify the purpose of the site. Conversion is always important to keep in mind and finding those points on the site where we want to convert people is key. Google.com is a great example of a simple looking site that has a user friendly interface as a top priority. They realize that by keeping a minimalist layout, you're eliminating distractions and increasing opportunities to hit the conversion goals on that particular page - a search, for example. The goals and user emphasis on Google will clearly be different than on a news based site. Here's what Google would look like if it optimized for SEO:

By defining a purpose of a page prior to design, you can make the design that much more effective, drawing attention to particular areas and away from others.