Imagination Games
Many games require nothing more than your imagination. I Spy may be a game that's generally played in the car, but if you have young children, this simple game can keep them entertained for hours. The Alphabet Story game can be a great game for older children, as well as younger children. Pick a letter to start with, and begin each word with the next letter to tell a story ("A big cat dances everywhere Freddy goes.")
Card Games
Most card games are easy to play and, so long as you don't drop the cards, easy to clean up when it is time to get off the plane. If you have young children, a simple game of "Go Fish" can keep everyone entertained for hours on end. If you are traveling with more mature companions, you could always try out a new game that you haven't played before, like Euchre or Five-Card Draw.
Printable Games
If you are traveling alone, printable games are probably the best option for you: from Sudoku to crossword puzzles, you have dozens of options to choose from. Many websites let you let you print free puzzles to take on the plane, and a few sheets worth of puzzles can keep you busy for the entire trip.
Digital Games
If you own a tablet or a smart phone, you have hundreds of games at your fingertips right now. Check out the game sections of the Apple App Store or the Android Market for plenty of fun games that you can get for free, or in some cases, just 99 cents. Be sure to bring a charger. You wouldn't want to land in a strange city with a dead battery.