RYTHROPOIETIN (EPO) is the principal growth factor E that promotes the viability, proliferation, and differentiation of mammalian erythroid progenitor cells, functions that are transduced by the specific cell surface EPO receptor (EPO-R). In contrast to many other hematopoietic growth factors, EPO primarily affects relatively mature erythroid cells, although it may also influence the growth and behavior of other cells. The recent cloning of the EPO-R gene has greatly facilitated the molecular analysis of the structure and function of this receptor, and provided a fundamental link to earlier biochemical and cellular studies of erythropoiesis. Here we describe recent studies on the structure, function, and activation of this receptor. One focus will be on mechanisms by which the activated receptor can induce cellular proliferation in the absence of EPO. This can be achieved by binding of a retrovirus envelope glycoprotein to the EPO-R or by a specific point mutation in the exoplasmic domain of the EPOR. EPO-independent activation of the EPO-R can contribute to the development of erythroleukemia in animal model systems. A second focus will be on the structure and control of expression of the EPO-R gene.