The epidermal growth factor (EGF) receptor is activated not only by EGF-like ligands, but also by stimuli that do not directly act on the receptor, including agonists of G protein–coupled receptors and certain environmental stresses such as ionizing radiation. Carpenter discusses two reports that indicate EGF receptor activation by such heterologous stimuli may occur through the action of proteases that release cell surface EGF-like growth factor precursors. This mechanism of EGF receptor transactivation appears to involve the generation of soluble agonists.