While nothing will ever replace them, classic sci-fi schlock like Plan 9 from Outer Space has probably inspired more modern cinema and video games than true classics like Earth vs. the Flying Saucers. The parodies are constant, and Destroy All Humans runs with just that. It's been regarded as Grand Theft Auto with an alien, and it's hard to find a better description.
Players take control of a dying alien race (they have no genitalia), and they need Earth people so they can expand their cloning operations. It's with this set up that gamers wreak havoc on a hilariously ignorant towns people, concerned more with communism and radiation than any alien threat. From a third person perspective, Krypto unleashes hell, snapping brain stems (complete with green goop) from unsuspecting victims to seal away their DNA.
The basic mission structure sets up well, dropping the little gray alien into 1950s suburbia where his actions commence. He has multiple items to do his bidding, and plenty more become available as time moves on. From a wide variety of guns (including a perfect vaporizing ray, a homage to George Pal's 1953 version of War of the Worlds) to telepathic powers used to manipulate his environment, there's never a dull moment.
With a well set-up and easy to master control scheme in use, you're never lost as to what offensive maneuvers are needed. While basic defense is as always just strafing, the more damage you cause (and the more authorities are alerted to your presence), the bigger the battle. At the worst, government agents begin using your own weapons against you.
When that happens and the opportunity permits, hop into your UFO and blow up everything. Tanks, mobile missile launchers, and hicks with shotguns will all try to take you down. The early going doesn't provide much outside basic ray firing, but when the ship's repertoire increases, so does the fun factor. That's because of a slow learning curve that eases players into the game instead of overwhelming them in the first few levels.