Human genetic diversity is the result of population genetic forces. This genetic variation influences disease risk and contributes to health disparities. Autoimmune diseases (ADs) are a family of complex heterogeneous disorders with similar underlying mechanisms characterized by immune responses against self. Collectively, ADs are common, exhibit gender and ethnic disparities, and increasing incidence. As natural selection is an important influence on human genetic variation, and immune function genes are enriched for signals of positive selection, it is thought that the prevalence of AD risk alleles seen in different population is partially the result of differing selective pressures (for example, due to pathogens). With the advent of high-throughput technologies, new analytical methodologies and large-scale projects, evidence for the role of natural selection in contributing to the heritable component of ADs keeps growing. This review summarizes the genetic regions associated with susceptibility to different ADs and concomitant evidence for selection, including known agents of selection exerting selective pressure in these regions. Examples of specific adaptive variants with phenotypic effects are included as an evidence of natural selection increasing AD susceptibility. Many of the complexities of gene effects in different ADs can be explained by population genetics phenomena. Integrating AD susceptibility studies with population genetics to investigate how natural selection has contributed to genetic variation that influences disease risk will help to identify functional variants and elucidate biological mechanisms. As such, the study of population genetics in human population holds untapped potential for elucidating the genetic causes of human disease and more rapidly focusing to personalized medicine.