Domestication of plants and animals marks a major transition in human history that represents a vibrant area of interdisciplinary scientific inquiry. Consideration of three central questions about domestication—what it is, what it does, and why it happened—provide a unifying framework for diverse research on the topic. Domestication is defined in terms of a coevolutionary mutualism between domesticator and domesticate and is distinguished from related but ultimately different processes of management and agriculture. Domestication results in a range of genotypic, phenotypic, plastic, and contextual impacts that can be used as markers of evolving domesticatory relationships. A consideration of causal scenarios finds greater empirical support for explanatory frameworks grounded in niche-construction theory over those derived from optimal foraging theory.