All cells and even organelles selectively degrade proteins with highly abnormal conformations whose continued accumulation is potentially toxic. Such proteins may arise by mutations, incorrect folding or postsynthetic damage. In eukaryotes, degradation of most proteins involves ubiquitin conjugation which marks the substrate for hydrolysis by the 26S proteasome. Despite dramatic progress in this area, it is still unclear how such abnormal proteins are recognized and selectively destroyed. It is now firmly established that molecular chaperones, in addition to their key roles in protein folding and targeting, are essential in the selective degradation of abnormal proteins. The collaboration between chaperones and the cell’s degradation machinery to efficiently eliminate abnormal proteins comprises a key protective mechanism that is important for cell viability. In various inherited and neurodegenerative diseases, the failure to eliminate unfolded proteins leads to the formation of protein inclusions, which can interfere with normal cell function, activate stress kinases, and induce apoptosis. Findings from the Goldberg group indicate that chaperones of the Hsp70, 40 (DnaJ), and 60 (GroEL) families function in protein breakdown either in the recognition of unfolded substrates or as cofactors or unfoldases that enhance the substrate’s susceptibility to cell ubiquitination enzymes, a full understanding of protein degradation will require greater knowledge about the precise roles of the different chaperones in the degradation of different types of proteins. A primary goal of our studies is to understand how the same chaperones can facilitate either the proper folding of a protein or its degradation.