Cells maintain a healthy proteome through continuous evaluation of the quality of each of their proteins. Quality control requires the coordinated action of chaperones and proteolytic systems. Chaperones identify abnormal or unstable conformations in proteins and often assist them to regain stability. However, if repair is not possible, the aberrant protein is eliminated from the cellular cytosol to prevent undesired interactions with other proteins or its organization into toxic multimeric complexes. Autophagy and the ubiquitin/proteasome system mediate the complete degradation of abnormal protein products. In this article, we describe each of these proteolytic systems and their contribution to cellular quality control. We also comment on the cellular consequences resulting from the dysfunction of these systems in common human protein conformational disorders and provide an overview on current therapeutic interventions based on the modulation of the proteolytic systems.