Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells(1). It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade(2). The half-maximal response in a cellular proliferation assay is evoked at an erythropoietin concentration of 10 pM (ref. 3), 10(-2) of its K-d value for erythropoietin-EPOR binding site 1 (K-d approximate to 1 nM), and 10(-5) of the K-d for erythropoietin-EPOR binding site 2 (K-d approximate to 1 mu M)(4). Overall half-maximal binding (IC50) of cell-surface receptors is produced with similar to 0.18 nM erythropoietin, indicating that only similar to 6% of the receptors would be bound in the presence of 10 pM erythropoietin. Other effective erythropoietin-mimetic ligands that dimerize receptors can evoke the same cellular responses(5,6) but much less efficiently, requiring concentrations close to their K-d values (similar to 0.1 mu M). The crystal structure of erythropoietin complexed to the extracellular ligand-binding domains of the erythropoietin receptor, determined at 1.9 Angstrom from two crystal forms, shows that erythropoietin imposes a unique 120 degrees angular relationship and orientation that is responsible for optimal signalling through intracellular kinase pathways.