Human illnesses affect men and women differently. In some cases (diseases of sex organs, diseases resulting from X or Y chromosome mutations), reasons for sex discrepancy are obvious, but in other cases no reason is apparent. Explanations for sex discrepancy of illness occur at different biological levels: molecular (e.g., imprinting, X-inactivation), cellular (sex-specific receptor activity), organ (endocrine influences), whole organism (size, age), and environmental-behavioral, including intrauterine influences. Autoimmunity represents a prototypical class of illness that has high female-to-male (F/M) ratios. Although the F/M ratios in autoimmune diseases are usually attributed to the influence of estrogenic hormones, evidence demonstrates that the attributed ratios are imprecise and that definitions and classifications of autoimmune diseases vary, rendering at least part of the counting imprecise. In addition, many studies on sex discrepancy of human disease fail to distinguish between disease incidence and disease severity. In April 2001, the Institute of Medicine of the National Academy of Sciences published Exploring the Biological Contributions to Human Health: Does Sex Matter? (Wizemann T and Pardue M-L, editors). This minireview summarizes the section of that report that concerns autoimmune and infectious disease. Some thyroid, rheumatic, and hepatic autoimmune diseases have high F/M ratios, whereas others have low. Those that have high ratios occur primarily in young adulthood. Gonadal hormones, if they play a role, likely do so through a threshold or permissive mechanism. Examples of sex differences that could be caused by environmental exposure, X inactivation, imprinting, X or Y chromosome genetic modulators, and intrauterine influences are presented as alternate, theoretical, and largely unexplored explanations for sex differences of incidence. The epidemiology of autoimmune diseases (young, female) suggests that an explanation for sex discrepancy of these illnesses lies in differential exposure, vulnerable periods, or thresholds. Biologists have an opportunity to inform medical scientists about sex differences that explain different attack rates in specific diseases, and physicians offer biologists experiments of nature to test theories of sex.