Molecular chaperones are a diverse group of multidomain proteins that assist in protein folding, protect subunits from heat shock during complex assembly, prevent protein aggregation, and mediate targeted unfolding and disassembly. Their increased expression in response to stress is crucial for cellular health and longevity. Unlike enzymes with specific active sites, chaperones are molecular machines that operate on a wide range of substrates. The structural basis of their action, particularly for heat shock proteins (HSPs) HSP60, HSP70, HSP90, and HSP100, involves large domain movements and rotations. Protein quality control, or proteostasis, involves the regulation of protein synthesis, folding, unfolding, and turnover, mediated by chaperone and protease systems, as well as cellular clearance mechanisms like autophagy and lysosomal degradation. These systems are essential for maintaining protein function and preventing the harmful effects of misfolded proteins, which can cause cell death in neurodegenerative diseases. Chaperones, such as HSP70, HSP90, HSP60, and HSP100, play key roles in these processes, with HSP70 being the most abundant and versatile chaperone. HSP70 coordinates cellular functions by directing substrates for unfolding, disaggregation, refolding, or degradation, while HSP90 integrates signaling functions and acts at late stages of folding. HSP60 acts at early stages of folding and provides a highly coordinated and symmetric allosteric machine. HSP100 is a sequential 'threading' machine for unfolding, cooperating with proteases or HSP70 for disaggregation. The mechanisms of action and allostery of these chaperones are being increasingly understood, but many questions remain, such as the nature of cytotoxic species that result from protein homeostasis failure.Molecular chaperones are a diverse group of multidomain proteins that assist in protein folding, protect subunits from heat shock during complex assembly, prevent protein aggregation, and mediate targeted unfolding and disassembly. Their increased expression in response to stress is crucial for cellular health and longevity. Unlike enzymes with specific active sites, chaperones are molecular machines that operate on a wide range of substrates. The structural basis of their action, particularly for heat shock proteins (HSPs) HSP60, HSP70, HSP90, and HSP100, involves large domain movements and rotations. Protein quality control, or proteostasis, involves the regulation of protein synthesis, folding, unfolding, and turnover, mediated by chaperone and protease systems, as well as cellular clearance mechanisms like autophagy and lysosomal degradation. These systems are essential for maintaining protein function and preventing the harmful effects of misfolded proteins, which can cause cell death in neurodegenerative diseases. Chaperones, such as HSP70, HSP90, HSP60, and HSP100, play key roles in these processes, with HSP70 being the most abundant and versatile chaperone. HSP70 coordinates cellular functions by directing substrates for unfolding, disaggregation, refolding, or degradation, while HSP90 integrates signaling functions and acts at late stages of folding. HSP60 acts at early stages of folding and provides a highly coordinated and symmetric allosteric machine. HSP100 is a sequential 'threading' machine for unfolding, cooperating with proteases or HSP70 for disaggregation. The mechanisms of action and allostery of these chaperones are being increasingly understood, but many questions remain, such as the nature of cytotoxic species that result from protein homeostasis failure.