In addition to their role in folding, there is evidence that chaperones participate in the degradation of damaged or misfolded proteins. While progress has been made in identifying components of the ubiquitin-proteasome system, there are few insights into how unfolded polypeptides are targeted to the degradation machinery. Upon translation there may be mechanisms that establish a hierarchy between the folding and degradation machineries. The unfolded state itself is unlikely to be the trigger for degradation, particularly since precursor proteins targeted for translocation across membranes are prevented from folding and yet are not ubiquitinated and degraded. We are currently investigating the mechanisms underlying the degradation of misfolded proteins using a combination of genetic and biochemical techniques.