Although they accomplish the same purpose for the end user, travel websites have different 'structures'. Kayak and SkyScanner for instance are 'travel search engines' - they simply search multiple airline websites, hotel sites, other online travel agents etc and then present the results. You'll notice that once you click on a result, you will be redirected to another website to complete the booking.
Expedia, Orbitz, Travelocity etc are all 'online travel agencies' - they function like real-world travel agencies in the sense that they file travel itineraries with airlines in the same way travel agent booking partners do. This means you can call / contact these sites for support, and often - depending on the airline - the only way to make changes is through the travel agent. On some international airlines, booking through an online travel agent means you won't be able to use web check-in facilities. etc.
The advantage of online travel agent sites is that they can negotiate cheaper fares with specific airlines directly - offers that you find elsewhere. This is particularly useful in certain verticals. For instance, STA Travel, an online/offline travel agent aimed at students - while fairly expensive for most other things - offers very discounted rates with select airlines; I've been able to get cheaper rates even when booking close to flight departure date. Similarly, many of the other bigger online travel agents also negotiate rates at times that can be better than what the airline's own website offers. Essentially, this is the problem search engines like Kayak are trying to solve by aggregating prices from different sources.
The catch is that because online travel agencies need to negotiate tie-ups with airlines, you may not find all existing flights on their site if they don't partner with that airline; this is especially true for international travel. Using a travel search engine thus usually gives a broader range of results, but keep in mind that many budget airlines often accept bookings exclusively through their own website and won't even show up on Kayak or Expedia. So it's always useful to search up a list of low-cost airlines operating in the region you're flying to and checking their websites individually.