In the past couple of years I have tried using a grid from scratch. However, I inevitably create the design until it feels right and then apply a grid retrospectively. Invariably — well, the half dozen times I've tried it — there is a grid that fits. And once you have a grid in place, then it's a breeze to create further pages and add additional elements.
Take, for example, a responsive portfolio site I created for the artist Laurence Wood. I created it in Fireworks until it seemed right, and then added a grid using the excellent Grids extension for Fireworks. There is an equivalent extension for Photoshop called GuideGuide. Turns out I was using a 27-column, 24-pixel column width and 12-pixel gutter, and I didn't even realise it.
So my advice is do what feels right. If that means starting out with a grid, all well and good. But don't be shy of trusting the inner feeling of something being correct. Heck, you could even do some sketches with a pencil.