Mitogens control progression through the cell cycle in non-transformed cells by complex cascades of intracellular messengers, such as Ca2+ and protons, and by cell volume changes. Intracellular Ca2+ and proton concentrations are critical for linking external stimuli to proliferation, motility, apoptosis and differentiation. This review summarizes the role in cell proliferation of calcium release from intracellular stores and the Ca2+ entry through plasma membrane Ca2+ channels. In addition, the impact of intracellular pH and cell volume on cell proliferation is discussed.