Mass extinctions are caused by significant environmental changes. Sometimes these changes are man-made, such as a factor that begins to pollute the water source. Other times these changes are natural, such as a disease or temperature change. One example in the news today has to do with frogs. There is a bacterial infections that is killing the world's frog population in record numbers. So far, this bacteria does not seem to jump species nor do we really understand where it is coming from. All scientists know right now is that the disease is deadly to frogs and the loss of frogs is causing a hole in the ecosystem of many areas.
Mass extinctions have occurred many times during the course of Earth's history. Specifically, when most of life is wiped out, it is due to something environmental that occurs that most organisms are unable to adapt to. It could be due to climate change--periods of ice age, or periods of higher temperatures. It could be due to an event that causes other events to occur--example, if a large asteroid hit earth, the dust would darken the skies, photosynthesis would decrease, temperatures too would decrease, the food chains may begin to fail and many organisms could die off. This possibly occurred when dinosaurs died out 65 million years ago.
Mass extinction can be caused by natural disasters and/or human-made (like weapons of mass destruction). By creating weapons which could exterminate life, life on earth as we know it could end. That being said, the climatic changes which are taking place on the earth could be responsible for mass extinction as well.
It takes a significant environmental change for a mass extinction to occur. This change could be due to manmade circumstances or natural changes in the environment, such as changes in climate.
Sometimes extinctions are indirectly caused. If pollution drastically reduces one species that happens to be the food source for another species, the second species may be the one that becomes extinct.
I don't think we know in all cases. We think that the mass extinction of the dinosaurs was caused by the asteroid hitting. We're pretty sure that the mass extinction of various animals in the Americas and Australia were caused by human actions. But there's not one answer as to what causes mass extinctions in general.