The main regulatory hormone for the control of erythropoiesis is erythropoietin (EPO). This glycoprotein has a molecular weight of 34,000 daltons, about 40% of which is represented by carbohydrates. EPO leads to an enhanced mitosis and differentiation of erythroid precursors (colony-forming unit erythroid) in the bone marrow by binding to specific receptors. The major stimulus for EPO formation in the kidney is hypoxia. The tubular parts that are intimately involved in this O2-sensing mechanism are the proximal tubular cells as can be inferred from the use of site-specific transport inhibitors. The minimal time necessary for a hypoxic signal to induce EPO formation was found to be 30 min, including wash out of oxygen stores, activation of the EPO gene and equilibration of the EPO distribution space. About 1.5 h after the onset of hypoxia, EPO mRNA was found to accumulate in the kidney, thus pointing toward the possibility of an oxygen-regulated transcription or oxygen-dependent regulation of the stability of EPO mRNA. Possibly, a decrease in the intracellular calcium concentration is involved in this signalling process.