The main function of red blood cells (RBC) is the transport of oxygen (O2) from the lung to peripheral tissues by means of hemoglobin (Hb). Transport needs to be adjusted to special situations such as hypoxia at high altitude and exercise to compensate for reduced availability and increased demand, respectively. These situations require specific and seemingly opposing adjustments to the O2 transport system. In hypoxia, when alveolar O2 is low, the binding of O2 by hemoglobin in the lung needs to be favored. In contrast, during exercise, the release of O2 from Hb needs to be optimized for maximal delivery to working muscle, where the O2 demand is high. The combination of both, i.e., exercise in hypoxia, represents a special challenge pushing the means of adjustments to its limits. Tissue O2 supply by RBC might even become insufficient. Adjustments of O2 transport by RBCs to these situations occur at three more or less independent levels, following a timed pattern: within seconds, O2 affinity of hemoglobin changes favoring binding and unloading as RBCs pass through lung and peripheral blood capillaries. Within minutes to days, plasma volume decreases to increase hematocrit (Hct), which raises the amount of O2 delivered per stroke volume. Long-term adjustments occur by increasing the number of RBCs and the total Hb mass by stimulation of erythropoiesis, which further improves tissue O2 supply.