There are too many variables for a simple answer, you need at least one thing certain or you'll be going around in circles.
My starting point is always date because I don't have much flexibility although I can plan way ahead. Others may be flexible on dates but rule out certain locations.
From the dates I just go through all the airlines (except Ryanair) around 3-4 months ahead and see who's got what. If I can find a bargain I check out accomodation with the local tourist office to get a feel for the market. Normally I'd book direct with the place but sometimes use
http://www.hrs.com (for small places they may be the same price but can confirm bookings straight away), a couple of times I've used expedia.