The formation and duration of binary receptor-ligand complexes are fundamental to many physiologic processes. Most often, the effectiveness of interaction between a receptor and its ligand is quantified in terms of closed system, equilibrium affinity measurements, such as IC50 and Kd. In the context of in vivo biology, however, the extent and duration of responses to receptor-ligand interactions depend greatly on the time period over which the ligand is in residence on its receptor. Here we define receptor-ligand complex residence time in quantitative terms and describe its significance to biological function. Examples of the importance of residence time are presented for natural ligands of different receptor types. The impact of residence time on the optimization of potential ligands as drugs for human medicine is also described.