Gastrin, produced by G cells in the gastric antrum, has been identified as the circulating hormone responsible for stimulation of acid secretion from the parietal cell. Gastrin also acts as a potent cell-growth factor that has been implicated in a variety of normal and abnormal biological processes including maintenance of the gastric mucosa, proliferation of enterochromaffin-like cells, and neoplastic transformation. Here, we review the models used to study the effects of gastrin on cell proliferation in vivo and in vitro with respect to mechanisms by which this hormone might influence normal and cancerous cell growth. Specifically, human and animal models of hypergastrinemia and hypogastrinemia have been described in vivo, and several cells that express cholecystokinin (CCK)B/gastrin receptors have been used for analysis of intracellular signaling pathways initiated by biologically active amidated gastrins. The binding of gastrin or CCK to their common cognate receptor triggers the activation of multiple signal transduction pathways that relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades, including mitogen-activated protein kinase, is an important early response to these signaling peptides. Gastrin and CCK also induce rapid Rho-dependent actin remodeling and coordinate tyrosine phosphorylation of cellular proteins including the non-receptor tyrosine kinases p125fak and Src and the adaptor proteins p130cas and paxillin. This article reviews recent advances in defining the role of gastrin and CCK in the control of cell proliferation in normal and cancer cells and in dissecting the signal transduction pathways that mediate the proliferative responses induced by these hormonal GI peptides in a variety of normal and cancer cell model systems.