Since in 1986 it was reported that a pertussis toxin-sensitive substrate was involved in the Ca2+ signal induced by epidermal growth factor (EGF) in rat hepatocytes, much evidence accumulated to implicate heterotrimeric G-proteins in EGF action. EGF can also induce a cyclic AMP signal, but while the generation of a Ca2+ signal appears to be quite general in EGF action, the increase in cyclic AMP occurs only in few cell types. In non-transformed cell types these effects appear to involve G-proteins. EGF not only induces cell proliferation but also interacts with hormones in the short-term control of cell function in quiescent cells. Most of the known interactions are on cyclic AMP mediated hormone effects, and in many cases, the interaction between EGF and hormones involves G-proteins. Here we review the evidence accumulated in recent years that implicate G-proteins in EGF action. An understanding of the mechanisms involved may reveal new mechanisms of G-protein regulation and will contribute to our knowledge of EGF function and signal transduction.