Growth factors are polypeptides that combine with specific membrane receptors on animal cells to stimulate proliferation, but they also stimulate glucose transport, uridine phosphorylation, intermediary metabolism, protein synthesis, and other processes of the coordinate response. There are a variety of nonspecific surface action treatments which stimulate the same set of reactions as the growth factors do, of which protein synthesis is most directly related to the onset of DNA synthesis. Mg(2+) is required for a very wide range of cellular reactions, including all phosphoryl transfers, and its deprivation inhibits all components of the coordinate response that have so far been tested. Growth factors raise the level of free Mg(2+) closer to the optimum for the initiation of protein synthesis. The resulting increase in protein synthesis accelerates progression through G1 to the onset of DNA synthesis and mitosis. None of the other 3 major cellular cations are similarly involved in growth regulation, although internal pH may play an auxiliary role. Almost 10(5) externally bound divalent cations are displaced from membranes for every attached insulin molecule, implying a conformational membrane change that releases enough Mg(2+) from the internal surface of the plasma membrane to account for the increase in free cytosolic Mg(2+). It is proposed that mTOR, the central control point for protein synthesis of the PI 3-K kinase cascade stimulated by insulin, is regulated by MgATP(2-) which varies directly with cytosolic Mg(2+). Other elements of the coordinate response to growth factors such as the increased transport of glucose and phosphorylation of uridine are also dependent upon an increase of Mg(2+). Deprivation of Mg(2+) in neoplastically transformed cultures normalizes their appearance and growth behavior and raises their abnormally low Ca(2+) concentration. Tight packing of the transformed cells at very high saturation density confers the same normalizing effects, which are retained for a few days after subculture at low density. The results suggest that the activity of Mg(2+) within the cell is a central regulator of normal cell growth, and the loss of its membrane-mediated control can account for the neoplastic phenotype.