Although the proteasome is responsible for the majority of intracellular protein degradation, and has been demonstrated to play a pivotal role in a diverse array of cellular activities, the role of the proteasome in the central nervous system is only beginning to be elucidated. Recent studies have demonstrated that proteasome inhibition occurs in numerous neurodegenerative conditions, and that proteasome inhibition is sufficient to induce neuron death, elevate intracellular levels of protein oxidation, and increase neural vulnerability to subsequent injury. The focus of this review is to describe what is currently known about proteasome biology in the central nervous system and to discuss the possible role of proteasome inhibition in the neurodegenerative process.