There were 5 major times in history that mass extinctions occured.
These were in the:
1) Late Ordovician
3) End of the Permian
4) Late Triassic
5) End of the Cretaceous
The Permian extinction was the largest and killed off 90% of the Earth's species. The cause is believed to be related to life already being stressed by a very dry climate, accompanied by prolonged periods of volcanic activity (the Siberia flood basalts).
The End Cretaceous extintion is the most famous as it is what ended the dinosaurs. The most common belief is that the cause was a 11km wide comet striking the Earth. However this is hottly debated as at the same time their was also a long period of volcanic activity in what is now India (the Decan Traps). Also some say that the rise of small mammals ended the dinosaurs by raiding their nests. It is possible that all these played a role.
The exact cause of many mass extintions is still being activly studied and debated by scientists