Clinical observation and epidemiological data support that susceptibility to disease and mortality are associated to the sex of the subject. In humans, women show longer longevity and are more resistant against infections and cancer, diseases in which immunity plays an essential protective role. By contrast, women are more susceptible to autoimmune diseases, which develop typically at reproductive age and are modified by the menstrual cycle and gestation. Complex interactions among the nervous, endocrine and immune systems contribute to the maintenance of homeostasis and integrity of the organism every instant. The knowledge of these sex differences is important not only to better understand the evolution of the adaptive immune system in vertebrates, but to grasp on the pathophysiology of immune-based diseases from a more integrated perspective and in order to develop more effective therapeutical strategies for the individual patient.