Growth factors and their transmembrane receptor tyrosine kinases play important roles in cell proliferation, survival, migration and differentiation. One group of growth factors, comprising epidermal growth factor (EGF)-like proteins and neuregulins, stimulates cells to divide by activating members of the EGF receptor (EGFR) family, which consists of the EGFR itself and the receptors known as HER2–4. This highly conserved signalling module plays a fundamental role in the morphogenesis of a diverse spectrum of organisms, ranging from humans to nematodes, and has also been implicated in the development and growth of many types of human tumour cells. In humans, more than 30 ligands and the EGFR family of four receptors lie at the head of a complex, multi-layered signal-transduction network. Different activated receptor–ligand complexes vary in both the strength and type of cellular responses that they induce. Analysis of the multiple processes that modulate EGFR signal transduction, such as receptor heterodimerisation and endocytosis, has revealed new therapeutic opportunities and elucidated mechanisms contributing to the efficacy of existing anticancer treatments.