In order to survive and maintain cellular homeostasis the different cells of the central nervous system (CNS) must continually adapt to a wide variety of genetic and environmental stimuli. Heat shock proteins (HSPs) are a class of proteins that are rapidly elevated in response to stress, aiding in protein folding, protein unfolding, and protein trafficking. The proteasome is a large intracellular protease that is responsible for the majority of intracellular protein degradation in the CNS. In particular, the proteasome is responsible for the degradation of most oxidized, aggregated, and damaged proteins. Increasing evidence suggests that HSPs may play important roles in the targeting of proteins to the proteasomal and lysosomal proteolytic pathways. Additionally, HSPs may play an important role in protein unfolding necessary for proteasome-mediated proteolytic degradation. Because the proteasome appears to become inhibited in a wide variety of neurodegenerative conditions, and possibly contribute to neurodegeneration in those conditions, studies must be conducted to determine how alterations in HSPs may contribute to proteasome inhibition in neurodegenerative disorders. The focus of this review is to outline what is currently known about HSPs and proteasome function in normal and neurodegenerative settings, and to discuss the possible therapeutic benefit of maintaining a robust HSP-proteasome interplay within the CNS.