Use the metaphor of resources to determine consistent, implementable URL and URI patterns for your pages. Sketch your site's map. But only just sketch. If you don't understand how this relates to your design, consider that "pages" is just a metaphor itself and the branches of site map don't necessarily mean "page".
Lay out for substantive content first.
Get specifications for the devices you expect to support for access to your information. Generalize the specifications into a set of parameters characterizing a category of media, rather than device. Create a style profile for each generalized category of media space. You might have a Desktop space, a high-definition smartphone space, a low-definition mobile space, a tablet space, etc. Consider each profile a proxy for one of your audiences.
Define your profiles incrementally. Choose a grid or columnar layout, and flow content into place.
Apply a strategy using Occam's Razor to your code:
pluralitas non est ponenda sine necessitateWhich is to say, don't use more markup than absolutely necessary to convey the meaning of the message. Use CSS for style. Don't use DIVs for positioning or include other gratuitous markup for layout tricks. Don't rely upon the relative positions and parent/child relationships in the markup for style or layout effects beyond in-line layout.
Include a browser reset. That will eliminate browser-introduced pluralities. It is regrettable that as of the year 2010 CSS3 and HTML5 still make it difficult to follow the Occam's Razor principle. But even a critic can see the situation is improving.
Use Behavior Driven Development with scenarios to storyboard the site. Why is anyone looking? What do they need to do?