Although I just posted about how awesome Photoshop CS6 is shaping up to be for interface design work, this article about using Keynote for web design and layout presents a compelling alternative. This point alone rings true:

If you can’t do it Keynote, it is unlikely you could achieve it in HTML/CSS.

Not stated in the linked article but worth noting: Photoshop CS6 is going to cost me somewhere in the $900 range to upgrade from Design Premium CS4 (unless Adobe finally – pretty please! – lets you upgrade single applications instead of the entire suite). Keynote costs $20.