Females greatly outnumber males as sufferers of chronic pain. Although social and psychological factors certainly play a role in the differences in prevalence and incidence, biological differences in the functioning of the immune system likely underlie these observed effects. This Review examines the current literature on biological sex differences in the functioning of the innate and adaptive immune systems as they relate to pain experience. With rodent models, we and others have observed that male mice utilize microglia in the spinal cord to mediate pain, whereas females preferentially use T cells in a similar manner. The difference can be traced to differences in cell populations, differences in suppression by hormones, and disparate cellular responses in males and females. These sex differences also translate into human cellular responses and may be the mechanism by which the disproportionate chronic pain experience is based. Recognition of the evidence underlying sex differences in pain will guide development of treatments and provide better options for patients that are tailored to their physiology. © 2016 Wiley Periodicals, Inc.