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Development of ectodermal tissues in humans is a complex process regulated by interacting signaling pathways. This review adopts an evolutionary medicine framework to examine how genetic variation in components of the ectodysplasin A (EDA) signaling pathway may have conferred human evolutionary fitness during the last ice age, but today may present an evolutionary mismatch, contributing to modern chronic diseases. A missense substitution at amino acid 370 in the human EDA receptor (EDAR) gene (EDARV370A), which is very common in East Asian, Native American, and Latino populations, produces pleiotropic effects in ectodermal tissues such as hair, teeth, mammary glands, and skin appendages. Several hypotheses have been offered to explain the high frequency of EDARV370A, proposing selective advantages related to thermal regulation, mother-infant vitamin D transmission, and/or tooth shape. However, new insight suggests that the selective advantage could have involved EDAR's systemic and epithelial immune effects rather than embryonic effects alone. We explore the possibility that inflammatory effects associated with EDARV370A were the target of selection approximately 20 000 years ago, but that this selective advantage could now represent an evolutionary mismatch in the context of abundant caloric supply, resulting in chronic inflammation and a higher risk of metabolic syndrome. Finally, we outline directions for future research.