Relatively few studies have been conducted to examine cholesterol as a nutrient for cell growth. Clonal growth and serial passage of several cell lines have been reported to be promoted or even dependent on the availability of exogenous cholesterol. Most cells, however, are capable of synthesizing cholesterol. Even in the presence of serum, a certain amount of endogenous cholesterol synthesis can be detected. Serum contains highly variable amounts of cholesterol and its oxygenated derivatives. These oxysterols are known to repress sterol synthesis and inhibit cellular proliferation and differentiation. Quiescent cells synthesize little cholesterol. When cells are stimulated to proliferate, a cycle of sterol synthesis can be detected in the G1 phase of the cell cycle. Correlation between cell growth and sterol synthesis and the activity of the rate-limiting enzyme of the pathway, 3-hydroxy-3-methylglutaryl-CoA reductase, was observed. Total blockage of the enzyme activity by treatment of cells with potent oxysterols or compactin (competitive inhibitor of the enzyme) leads to inhibition of DNA synthesis and of cellular proliferation. Recent evidence has suggested that, besides cholesterol, the synthesis of several nonsterol isoprenoid compounds may also be required for cell growth and differentiation.