I kind of have to (Damn it!!!!) agree with Omega. One can create cool and crazy designs, but it needs to be practical. Besides, people are creatures of habit, and visitors tend to feel comfortable with familiar layouts. Vertical columns are very practical, headers basically help make it unique. I try real hard to make it unique, but it's hard when you have no creativity.
And I've heard it said before that CSS based designs aren't remarkable. I think this is unfair and gives people the wrong impression of CSS. CSS is powerful, however, the majority of designers don't particularly care and/or even know of CSS. One mostly fines mainly programmers or scripters into CSS. This is what CSS Zen Garden is trying to change, but we'll see.
I'd say one's best bet is to take the existing layouts we use and to make it as unique as possible. It is the little differences and touches that can make a site unique.