Having designed www.mogotix.com, which is completely responsive, I can say that fluid layouts absolutely create challenges that fixed layouts do not. That said, they're not insurmountable, and the benefits are substantial.
Two brief examples: 1. Try embedding a YouTube video into a fluid layout. You'll need a JavaScript solution to remove the ugly black bands that will appear above and below your video. 2. IE 6-8 do not support media queries, which form the basis for fluid layouts. When we relaunched MogoTix in March 2011, I had to include a jQuery script to get IE to understand media queries (that script is now included by default in the 1140px grid at cssgrid.net).
If anyone has questions about implementing a fluid layout, feel free to ask.