Erythropoietin (EPO) is the crucial cytokine regulator of red blood-cell production. Since the discovery of EPO in 1985 and the isolation of its cognate receptor four years later, there has been significant interest in understanding the unique ability of this ligand–receptor pair to promote erythroid mitogenesis, survival and differentiation. The development of knockout mice has elucidated the precise role of the ligand, receptor and downstream players in murine erythroid development. In this review, we summarize EPO-mediated signaling pathways and examine their significance in vivo.