One in every four deaths in the United States is attributed to heart disease and is associated with high serum cholesterol. High serum cholesterol can result from diets that are rich in cholesterol-containing foods or from biosynthesis of cholesterol in the liver. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyzes an early step in the cholesterol biosynthetic pathway. Inhibition of HMG-CoA reductase lowers intracellular cholesterol levels by reducing its synthesis. Structural, kinetic, and mechanistic studies are crucial to understand how enzymes such as HMG-CoA reductase function and to discover or design inhibitors of their activity. Studies of HMG-CoA reductase in the 1970s showed that some compounds similar to the natural substrate, HMG-CoA, were effective at reducing enzyme activity. This discovery paved the way for the development of a large class of HMG-CoA reductase inhibitors, the statin drugs, that are in widespread clinical use today. With detailed information about how inhibitors bind to enzymes and block their activity, new drugs with improved inhibitory actions are being designed.