One of the more interesting layouts I've seen lately goes back to the d20 Call of Cthulhu! First off, the cover is wonderful! Looks like it came directly out of Sam Raimi's Evil Dead! Wonderful work by Ann Koi and Jason Soles.
The layout is what struck me, though. Like most RPG books, its represented with two columns on each page. Pretty standard. But what is way different is that the columns are not straight! They are presented in angles. The first thing that came to mind was something from film school, the Dutch angle. Also known as the Dutch tilt or canted angle. Often used to portray uneasiness or tension. Also, often associated with crazy or mental or highly unusual.
While doing the research for this blog post, it came to my attention that this very book won two Ennies in 2002! It was nominated for Best d20 Game and actually won for Best Graphic Design and Layout! Credited to Robert Campbell and Dawn Murin. So there you have it...
All of that is perfect for Call of Cthulhu.