The proliferation of normal mammalian cells, similar to that of single bacterial and lower eukaryotic cells, is restricted by space and nutrients. Cultured human lung fibroblasts have been used as a model to show that, in the absence of spatial restrictions, the requirement for specific nutrients limits normal cell proliferation. Serum-derived hormonelike growth factors transiently reduce the requirement for Ca2+, K+, Mg2+, phosphate ions, and 2-oxocarboxylic acids for normal cell proliferation. Oncogenic transformation by virus causes a constitutive reduction in the requirement for multiple nutrients for proliferation. A constitutive reduction in the proliferative requirement for Ca2+, K+, and Mg2+ allows transformed cells to escape the restrictions imposed on normal cell growth by suboptimal external concentrations of Ca2+, K+, Mg2+, and hormonelike growth factors. An understanding of the processes that determine the nutrient requirements of different normal cell types and their alteration by hormonelike growth factors and oncogenic agents is needed to understand and suppress the growth advantage possessed by malignant cells.