Many clinicians have suboptimal knowledge of evolutionary medicine. This discipline integrates social and basic sciences, epidemiology, and clinical medicine, providing explanations, especially ultimate causes, for many conditions. Principles include genetic variation from population bottleneck and founder effects, evolutionary trade-offs, and coevolution. For example, host–microbe coevolution contributes to the inflammatory and carcinogenic variability of Helicobacter pylori. Antibiotic-resistant strains are evolving, but future therapy could target promutagenic proteins. Ancient humans practicing dairying achieved survival and reproduction advantages of postweaning lactase persistence and passed this trait to modern descendants, delegitimizing lactose intolerance as “disease” in people with lactase nonpersistence. Three evolutionary hypotheses are each relevant to multiple diseases: (i) the polyvagal hypothesis posits that prehistoric adaptation of autonomic nervous system reactions to stress is beneficial acutely but, when continued chronically, predisposes individuals to painful functional gastrointestinal disorders, in whom it may be a biomarker; (ii) the thrifty gene hypothesis proposes genetic adaptation to feast–famine cycles among Pleistocene migrants to America, which is mismatched with Indigenous Americans' current diet and physical activity, predisposing them to obesity, nonalcoholic fatty liver disease, and gallstones and their complications; and (iii) the hygiene hypothesis proposes alteration of the gut microbiome, with which humans have coevolved, in allergic and autoimmune disease pathogenesis; for example, association of microbiome-altering proton pump inhibitor use with pediatric eosinophilic esophagitis, early-life gastrointestinal infection with celiac disease, and infant antibiotic use and an economically advanced environment with inflammatory bowel disease. Evolutionary perspectives broaden physicians' understanding of disease processes, improve care, and stimulate research.