Among the molecules that determine the developmental fate of sympathetic neurons from noradrenergic to cholinergic function are two apparently unrelated proteins, cholinergic differentiation factor and ciliary neurotrophic factor (CDF and CNTF, respectively). The present work suggests a structural basis for their functional overlap: sequence pattern-matching and predictive structure analysis contends that CDF and CNTF are homologous and share a common helical framework. An integrated CDF/CNTF profile also reveals similar sequence/structure motifs in a group of hematopoietic cytokines composed of granulocyte colony-stimulating factor, interleukin-6, and a novel factor called oncostatin M; a more distant relationship is indicated with interleukin-3 and interferons-alpha/beta. Evolutionary ties between neuropoietic and hematopoietic cytokines predict a distinctive tertiary architecture for the uncharacterized CDF and CNTF receptors. The intertwined cytokine/receptor networks signal a closer relationship between the molecular mechanisms underlying neuro- and hematopoiesis.