Before you start to buy your plane tickets, keep a couple of things in mind.
First, don't forget that different airlines will charge you different fees. Sample fees will include:
MEALS: Some airlines charge you for all meals; some will offer 1 free meal for the same flight that another airline will give 2 free meals for. Some may have extra costs for special requests (Gluten-Free, etc.), some won't. Some offer only peanuts as their snack (which you may be allergic to), some actually provide several options for free.
2nd Suitcase: Airlines differ on whether or not they will allow you one free suitcase or two. This will also vary depending on where you are going and what country the airline is based in. Make sure you aren't going to be charged (sometimes as much as $100+) for your extra suitcase. You can find a list of some current luggage allowances here.
Overweight Luggage: Airlines also differ on how much weight you are allowed to carry. If you plan to bring a lot back, make sure you won't be charged (sometimes as much as the cost of a whole new bag) for overweight luggage.
Upgrades: If you are interested in upgrading your seat or paying for any little extras, then see what the fees will be. It's cheaper with some airlines than with others.
Wireless/Outlets: Some airlines (not many) offer free wireless on the planes or in the airports, but others are going to seriously charge you for the privilege.
Second,keep in mind the geography. You may not want to use an Asian airline to plan your trip to Europe. In the same vein, you may find that a European airline is cheaper regarding flights to Europe than a US airline, even if you're flying out of a US. Things to consider:
Airlines often offer cheaper luggage allowances for flights going to or from their home nation.
Upgrade fees though may be more expensive
Check to see if the destination country has flight search engines or travel agencies who offer better prices. You may find a better price with a EU travel company when flying there than you would by searching one of the US Search Engines.
Remember that less-visited locations may have cheaper flights. It might be cheaper to fly to a smaller town and catch a bus to the big city than to fly straight there. It was a lot cheaper to fly to Tianjin (1 hr from Beijing) and catch the bus to the capital rather than flying straight to the capital itself. On the other hand, the reverse may be true.
Third, remember the cheapest "Ticket" may not be the best/least expensive flight for you.
Combine everything you know about what the airlines offer and what you will need when shopping for flights. All those search engines and airlines are going to offer an estimate ticket cost, but that won't include those extra fees I was talking about. And the airline may not offer certain amenities you really need. So check out the airline, look at the seating room, the outlet availability, luggage fees, and all the things you have to have. Then add those additional fees to the total. You may find that the additional fee for a suitcase at one airline may make the total trip more expensive than at another airline who's base ticket was more expensive.
The Multi-City Search Tool is often NO GOOD! See the article here by Mike Masnick for a better explanation.
NO SEARCH ENGINE IS THE SAME. The airlines will offer different fees from the search engines, the search engines are often going to disagree. They may offer the same price with different airline arrangements, etc. SHOP!!
Call the airlines before buying the ticket. Sometimes they'll compromise with you just so they don't have to pay the middle-man (Search Engine). Just have some estimate on hand to give them.
The one-stop flight is rarely the cheapest.
Layovers may sound really annoying, but don't necessarily compromise money for luxury. If the layover is long enough you can usually leave your bags at the airport and travel around a little (even 5 hours is good), and you can always bring a book or play on your laptop.
Don't over-estimate your powers of waking up. If you can't get up at 6:00 a.m., don't have a flight arranged for that time. The cost of missing your flight will outweigh the higher cost of a later ticket.