An important component of psychoneuroimmunology research is to reveal the myriad ways that behaviors and health are inter-related, with a focus on the immunological mechanisms that underlie these interactions. Research in human psychoneuroimmunology has shown that immunoregulatory processes are an integral part of a complex network of adaptive responses. As such, this review provides a perspective from our laboratory over the last 20 years to define the inter-relationships between behavior and immunity; to identify the hypothalamic pituitary adrenal (HPA) and autonomic mechanisms that link the central nervous system and immune responses; to examine the clinical implications of immune alterations during depression or life stress on inflammatory and infectious disease risk; and to explore the reciprocal role of immune mediators on behavior in humans.