The sigma-1 and sigma-2 receptors were first discovered in the 1960s and were thought to be a form of opioid receptors initially. Over time, more was gradually learned about these receptors, which are actually protein chaperones, and many of their unique or unusual properties can contribute to a range of important new therapeutic applications. These sigma receptors translocate in the body and regulate calcium homeostasis and mitochondrial bioenergetics and they also have neuroprotective effects. The ligands to which these sigma receptors respond are several and dissimilar, including neurosteroids, neuroleptics, and cocaine. There is controversy as to their endogenous ligands. Sigma receptors are also involved in the complex processes of cholesterol homeostasis and protein folding. While previous work on this topic has been limited, research has been conducted in multiple disease states, such as addiction, aging. Alzheimer's disease, cancer, psychiatric disorders, pain and neuropathic pain, Parkinson's disease, and others. There is currently increasing interest in sigma-1 and sigma-2 receptors as they provide potential therapeutic targets for many disease indications.