I started using OmniGraffle to produce wireframes over a year ago and haven’t looked back. I went from spending weeks creating greybox-style, perfect wireframe in Fireworks to being able to knock out 55 pages of wireframes in two days with a UX-heavy client.

Disclaimer: This is my current wireframing process for desktop-only sites. We, and everybody else, are still figuring the best scalable approach for responsive wireframing, although I believe that OmniGraffle can easily serve that purpose as well.

I once used Adobe Fireworks to produce wireframes and design comps, but found my creativity stifled when I duplicated my wireframe document to produce the comps. Although it saved me some time, I inherited too many of the design decisions from the wireframes; the end design would feel too boxy and, well, wireframey.