HMG-CoA reductase is the rate-limiting enzyme of cholesterol biosynthesis. The expression level of this membrane-bound enzyme is controlled by many factors that in turn regulate cholesterol synthesis and cellular cholesterol homeostasis. However, the most important mechanisms involve those that control the stability of the protein and transcription of the gene. Studies utilizing both mammalian cells and yeast have shown that increased degradation of HMG-CoA reductase occurs when cellular levels of either the 15-carbon isoprenoid farnesyl diphosphate (FPP), farnesol (dephosphoryled FPP), or an unidentified derivative of FPP are increased. The isoprenoid-dependent increase in degradation of both mammalian and yeast HMG-CoA reductase also requires an oxysterol.