Inflammation, a common denominator among the diverse list of neurodegenerative diseases, has recently been implicated as a critical mechanism responsible for the progressive nature of neurodegeneration. Microglia are the resident innate immune cells in the central nervous system and produce a barrage of factors (IL-1, TNFalpha, NO, PGE2, superoxide) that are toxic to neurons. Evidence supports that the unregulated activation of microglia in response to environmental toxins, endogenous proteins, and neuronal death results in the production of toxic factors that propagate neuronal injury. In the following review, we discuss the common thread of microglial activation across numerous neurodegenerative diseases, define current perceptions of how microglia are damaging neurons, and explain how the microglial response to neuronal damage results in a self-propelling cycle of neuron death.