Interleukin 3 (IL‐3) and granulocyte‐macrophage colony stimulating factor (GM‐CSF) exert their biological functions through acting on a specific receptor which consists of a ligand‐specific alpha subunit and the shared common beta subunit. Inhibition by genistein of a subset of IL‐3/GM‐CSF‐mediated signals, including c‐myc induction, resulted in the abrogation of DNA synthesis, however, IL‐3 still protected cells from apoptotic cell death. Conversely, a C‐terminal truncated form of the GM‐CSF receptor, which is missing a critical cytoplasmic region required for activation of the Ras/Raf‐1/MAP kinase pathway, induced DNA synthesis, but failed to prevent cell death in response to GM‐CSF. Consequently, cells died by apoptosis in the presence of GM‐CSF, despite displaying a transient mitogenic response. However, expression of activated Ras protein complemented defective signalling through the mutant receptor and supported long‐term proliferation in concert with GM‐CSF. These results indicate that IL‐3 and GM‐CSF prevent apoptosis of hematopoietic cells by activating a signalling pathway distinct from the induction of DNA synthesis and that long‐term cell proliferation requires the activation of both pathways.