Allometric scaling deals with the functional consequences of changes in size or scale among geometrically dissimilar animals (ie, animals differing in proportions). For adult mammals ranging in size and proportion from mouse to elephant, the data describe an interdependent set of functions consisting of metabolism (measured as metabolic rate), glomerular filtration rate (GFR), effective renal plasma flow, excretion of nitrogenous waste products, cardiac output, and pulmonary function-related variables. Within this set of functions, evidence indicates that metabolic rate is the primary process. One important design feature is given by the ratio of GFR to metabolic rate. Because this ratio is independent of size, it can be generalized to all mammals in this series. The numeric value of this ratio gives the optimal GFR for each unit of metabolic rate. A simple hypothesis is proposed: metabolic rate, the primary process, sets GFR. This relationship is unidirectional. A decrease in GFR, for example, caused by nephron loss, should not lead to a change in metabolic rate. This hypothesis was tested in four natural experiments: human growth and development, thyroid dysfunction, chronic renal failure, and hibernation. The results are consistent with this hypothesis.