A mathematical model for the control of erythropoiesis has been developed based on the balance between oxygen supply and demand at a renal oxygen detector which in turn controls erythropoietin release and red cell production. Tissue oxygen tension is regulated by adjustments of hemoglobin levels resulting from the output of a renal-bone marrow controller. Special consideration given to the determinants of tissue oxygenation included evaluation of the influence of blood flow, capillary diffusion, oxygen uptake, and oxygen-hemoglobin affinity. A theoretical analysis of the overall control system is presented including: a) dynamic and steady-state responses, b) sensitivity analysis to determine the relative importance of parameters and their influence on model behavior, c) properties of the model as a proportional controller, d) analysis of steady-state errors, and e) effectiveness of feedback regulation. Computer simulations of altitude hypoxia, descent from altitude, red cell infusion, and hemolytic anemia demonstrate the validity of the model for general human application.