Obey the the natural flow of a website
When designing a website in Fireworks or Photoshop you should keep in mind how things fall on their places in a browser.
HTML document in a browser is like river, it has natural way to flow. It obeys the rules of physics like a normal river, the physic is just written by engineers. Nevertheless, a page has its own artless flow how it sets; things align to left, how images set them self between the text, how floats behave etc.
What I’m saying is: I like the idea of obeying this flow in the design. Be as natural for the environment as you can and the design will looks solid and good.
Of course it can be fun to make wacky totally retarded layouts just to keep things interesting.