Intracellular protein quality control systems fighting against proteotoxic stress to avoid disruption of cellular functions by unfolded proteins. Under normal conditions, misfolded proteins can induce Hsp70 gene expression in order to be either refolded to native conformation or targeted for degradation if they are damaged beyond repair. The main cytosolic protein degradation pathway is represented by the ubiquitin-proteasome system (UPS). During protein degradation, both Hsp70 and Hsp90 bind to the cochaperone CHIP (carboxyl terminus of Hsp70-interacting protein), which serves as an E3 ubiquitin ligase by attaching a polyubiquitin chain to the irreparably damaged protein so that it can be targeted for proteasomal degradation. The proteasomal degradation process also requires the binding of BAG-1 (Bcl-2-associated athanogene) to the ATPase, N-terminal domain of Hsp70. Alternatively, CHIP may target misfolded proteins with a KFERQ motif for chaperone-mediated autophagy (CMA) by binding the heat shock cognate 70 (Hsc70 or Hsp73), which then guides the damaged proteins into the lysosome through the lysosomal-associated membrane transporter (LAMP2A). On the other hand, if proteins can be refolded into their native shape, BAG-1 binding to Hsp70 is blocked by the cochaperone Hip (Hsp70-interacting protein), whereas CHIP binding is blocked by the cochaperone Hop (Hsp70/90-organizing protein). Hsp40 and Hsp90 also bind to this protein refolding complex, promoting an ATP-dependent folding activity. Under conditions of overwhelming proteotoxic stress and defective protein degradation machineries, misfolded, damaged proteins may dramatically accumulate, aggregate, and kill cells.