This paper, the first of a series on the regulation of the hematopoietic stem cell, examines the effects of stem cell kinetics during an acute exposure to hypoxic-hypoxia. This physiologic perturbation was chosen because of the well-established role it plays in influencing erythropoiesis. BDF1 male mice were exposed to a simulated altitude of 22,000 ft for periods of time ranging from 3 to 48 hr. The following parameters were assessed: Packed red cell volume, number of nucleated cells per femur and spleen, relative and total number of colony-forming units (CFU, i.e., stem cells) in the femoral shaft and whole spleen, as well as the turnover of this population of cells using the "3H-thymidine-killing" technique. The spleen responds by releasing more than one-half (i.e., approximately 108 cells) of its prehypoxic complement of nucleated cells. On the other hand, the femoral cellularity did not decrease but showed a moderate increase. Within 12 hr of hypoxia exposure the total femoral CFU had markedly risen, in some cases between 50% and 75% above control levels. There were, nevertheless, great fluctuations over a short period of time. The population turnover kinetics revealed that after 3 hr of hypoxia an average of 25% of the CFU in both marrow and spleen were in the DNA synthetic phase. It is clear that stem cells are capable of responding rapidly to hypoxia. The possible regulatory mechanisms are discussed in terms of what is known about the kinetics of erythropoietin generation.