Medicine and clinical microbiology have traditionally attempted to identify and eliminate the agents that cause disease. However, this traditional approach is becoming inadequate for dealing with a changing disease landscape. Major challenges to human health are non-communicable chronic diseases, often driven by altered immunity and inflammation, and communicable infections from agents which harbour antibiotic resistance. This Review focuses on the so-called evolutionary medicine framework, to study how microbial communities influence human health. The evolutionary medicine framework aims to predict and manipulate microbial effects on human health by integrating ecology, evolutionary biology, microbiology, bioinformatics, and clinical expertise. We focus on the potential of evolutionary medicine to address three key challenges: detecting microbial transmission, predicting antimicrobial resistance, and understanding microbe–microbe and human–microbe interactions in health and disease, in the context of the microbiome.