Ligand-induced dimerization of cell surface receptors has emerged as a general mechanism for the initiation of signal transduction. A number of therapeutically important receptor families are believed to be activated by this process. Recently available structural information, particularly for the erythropoietin receptor, has provided insight into the mechanism of receptor activation. These findings have also revealed important constraints on the nature of receptor-agonist complexes. The prospects of discovering small-molecule mimetics of such receptor agonists are discussed, including strategies which have led to the identification of a small number of peptide and non-peptide cytokine mimetics.