The price paid by the cardiovascular system for maintaining circulation is being a target of chronic forces that contribute to wear and tear. Cardiovascular tissues are in constant peril of damage from these stresses, and are dependent on highly conserved cellular machines for protection. The cellular environment is adapted to detect, repair and, if necessary, dispose of damaged proteins, in part because they are toxic to the cell. The molecular chaperone and ubiquitin-proteasome systems are the machinery that repair and degrade damaged proteins, yet little attention has been given to these systems in cardiovascular pathophysiology. Recent advances have brought protein folding and degradation closer to the forefront of cardiovascular biology. This review discusses these advances and presents new models for consideration of cardiovascular pathophysiology and therapeutics as problems of protein homeostasis. In most cases, all the information necessary for a protein to fold is contained in its primary amino acid sequence. The environment within a cell is particularly unfavorable for protein folding, however, because of constraints that occur during protein synthesis and the likelihood of intermolecular interactions that impede folding in a crowded cellular environment. An evolutionarily ancient system exists to prevent damaged or newly synthesized peptides from aggregating and to provide a microenvironment that facilitates their proper folding to a thermodynamically favorable active conformation. This system comprises the molecular chaperones, which are present in every cellular compartment to buffer and repair damaged proteins (the Table provides a partial list of mammalian chaperones). Mechanisms for removing proteins are equally critical to cellular function, and the machinery of protein degradation is similarly archaic. Although several pathways exist for protein destruction in eukaryotes, the ubiquitin-proteasome system is responsible for the majority of protein degradation and is the most tightly regulated pathway. View this table: Examples of Mammalian Chaperones and Their Functions The chaperone and ubiquitin-proteasome …