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The heterogeneity of tissue macrophages, in health and in disease, has become increasingly transparent over the last decade. But with the plethora of data comes a natural need for organization and the design of a conceptual framework for how we can better understand the origins and functions of different macrophages. We propose that the ontogeny of a macrophage—beyond its fundamental derivation as either embryonically or bone marrow-derived, but rather inclusive of the course of its differentiation, amidst steady-state cues, disease-associated signals, and time—constitutes a critical piece of information about its contribution to homeostasis or the progression of disease.