The strong clinical activity of the proteasome inhibitor bortezomib (Velcade) in multiple myeloma and other hematological malignancies has focused considerable attention on its mechanisms of action. Although NFκB inhibition was initially the mechanism in focus, accumulating evidence indicates that misfolded protein accumulation leading to proteotoxicity plays an even more important role in cell killing. Proteotoxicity that occurs as a consequence of protein aggregate accumulation has long been associated with the development of neurodegenerative diseases, and a large and growing body of literature has documented how protein aggregates are handled and disposed of via evolutionarily conserved mechanisms involving cross talk between the proteasome and autophagy in normal cells. The type II histone deacetylase HDAC6 plays important roles in these processes and HDAC6 inhibition enhances proteotoxicity. These observations served as the basis for the development of HDAC6-specific chemical inhibitors that are now being evaluated in combination with proteasome inhibitors in preclinical models. Nonetheless, there is also strong evidence that the more classical, chromatin-associated (type I) HDACs are also involved in the regulation of proteotoxicity, although the biochemical mechanisms underlying their effects are not well defined. Importantly, emerging evidence indicates that subsets of tumor cells contain defects in these protein quality control pathways, which may underlie their vulnerability to proteasome inhibitor-induced death. In addition, our clearer understanding of cytoprotective protein quality control responses is identifying novel candidate targets for therapeutic intervention. In this chapter, we present an overview of protein quality control mechanisms in normal tissues and describe how this information is informing our development of proteasome inhibitors and other agents that impact upon these pathways for cancer therapy.