In this study, we modeled mathematically the transport of glucose across renal medullary vasa recta and its conversion to lactate by anaerobic glycolysis. Uncertain parameter values were determined by seeking good agreement between predictions and experimental measurements of lactate generation rates, as well as glucose and lactate concentration ratios between the papilla and the corticomedullary junction; plausible kinetic rate constant and permeability values are summarized in tabular form. Our simulations indicate that countercurrent exchange of glucose from descending (DVR) to ascending vasa recta (AVR) in the outer medulla (OM) and upper inner medulla (IM) severely limits delivery to the deep inner medulla, thereby limiting medullary lactate generation. If the permeability to glucose of OMDVR and IMDVR is taken to be the same and equal to 4 x 10(-4) cm/s, the fraction of glucose that bypasses the IM is calculated as 54%; it is predicted as 37% if the presence of pericytes in OMDVR reduces the glucose permeability of these vessels by a factor of 2 relative to that of IMDVR. Our results also suggest that red blood cells (RBCs) act as a reservoir that reduces the bypass of glucose from DVR to AVR. The rate of lactate generation by anaerobic glycolysis of glucose supplied by blood from glomerular efferent arterioles is predicted to range from 2 to 8 nmol/s, in good agreement with lower estimates obtained from the literature (Bernanke D and Epstein FH. Am J Physiol 208: 541-545, 1965; Bartlett S, Espinal J, Janssens P, and Ross BD. Biochem J 219: 73-78, 1984).