Psychoneuroimmunology (PNI) emerged in the neurosciences in the late 1970s to early 1980s and has extended to influence the fields of psychology, psychiatry, endocrinology, physiology, and the biomedical research community. This review documents the journey of PNI from the early 1980s to the present. Today, we recognize that the highly complex immune system interacts with an equally complex nervous system in a bidirectional manner. Evolutionarily old signals continue to play a role in these communications, as do mechanisms for protection of the host. The disparity between physical and psychological stressors is only an illusion. Host defense mechanisms respond in adaptive and meaningful ways to both. The present review will describe a new way of thinking about evolutionarily old molecules, heat shock proteins, adding to a body of evidence suggesting that activation of the acute stress response is a double-edged sword that can both benefit and derail optimal immunity.