Cells and organisms must be able to maintain protein homeostasis to ensure steady-state health and adaptation. Cancer, neurodegenerative, inflammatory and other diseases lead to perturbations of protein homeostasis and are often even promoted by them. Molecular chaperones are a family of proteins that are critically involved in maintaining and adjusting protein homeostasis in health and disease. Here we present these proteins, and review both their less desirable connections with diseases and the phenotypes of genetic alterations of the genes encoding them. Indeed, because molecular chaperones also contribute to diseased states, they have emerged as drug targets. We therefore provide an extensive overview of strategies that have been developed to modulate the activity of several types of molecular chaperones.