Resources
The tools I actually book through, sorted by what you're booking.
Google Flights · Skyscanner
For flights I use Google Flights and Skyscanner, almost nothing else. The real edge is the Explore feature on both: set your budget and see how far it gets you, or find the cheapest route across flexible dates.
One rule I don't break: book directly with the airline. If a flight gets delayed or cancelled, booking direct means the airline works with you directly. A third party just adds another layer between you and the fix.
Hotels.com · Agoda · Engine
Which site I reach for depends on where I am.
In the US, Hotels.com is my default: strong points program, global coverage. I don't stick to one chain, so traditional hotel loyalty programs do little for me. This earns across all of them.
In Asia, Agoda is the move. It's often cheaper than the western sites, with inventory that's hard to find elsewhere.
For work travel, Engine regularly has 20%+ off public hotel rates across the US. That's where I book when I'm traveling for business. Business travel only.
Kayak · Local companies
In the US, Kayak has been the most competitive, with the best range of options.
Internationally, I look for local companies instead. They give you the most flexibility. I've had someone meet me at the airport to hand over the car, and they'll often let you drop it at the airport or wherever else is convenient.
12go
For trains and buses, especially to off-the-beaten-path destinations, 12go is the one. Solid interface and wide coverage. When I had a problem with an Uzbek train ticket once, their support team sorted me out.
Direct Ferries
Direct Ferries is my default for any crossing. Global coverage, and the price is usually the same as booking direct with the operator. The difference is flexibility: they're easier on cancellations, even on basic tickets, than the ferry companies themselves. When my Corsica ferry got cancelled for high winds, they refunded me and got me rebooked.