The epidermal growth factor (EGF) system has allowed chemists, biologists, and clinicians to improve our understanding of cell production and cancer therapy. The discovery of EGF led to the recognition of cell surface receptors capable of controlling the proliferation and survival of cells. The detailed structures of the EGF-like ligand and the responses of their receptors (EGFR-family) has revealed the conformational and aggregation changes whereby ligands activate the intracellular kinase domains. Biophysical analysis has revealed the preformed clustering of different EGFR-family members and the processes which occur on ligand binding. Understanding these receptor activation processes and the consequential cytoplasmic signaling has allowed the development of inhibitors which are revolutionizing cancer therapy. This Review describes the recent progress in our understanding of the activation of the EGFR-family, the effects of signaling from the EGFR-family on cell proliferation, and the targeting of the EGFR-family in cancer treatment.