The domestication of plants and animals is a key transition in human history, and its profound and continuing impacts are the focus of a broad range of transdisciplinary research spanning the physical, biological, and social sciences. Three central aspects of domestication that cut across and unify this diverse array of research perspectives are addressed here. Domestication is defined as a distinctive coevolutionary, mutualistic relationship between domesticator and domesticate and distinguished from related but ultimately different processes of resource management and agriculture. The relative utility of genetic, phenotypic, plastic, and contextual markers of evolving domesticatory relationships is discussed. Causal factors are considered, and two leading explanatory frameworks for initial domestication of plants and animals, one grounded in optimal foraging theory and the other in niche-construction theory, are compared. Significance 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.