Squalene synthase catalyzes the reductive dimerization of famesyl diphosphate (C-15) to form squalene, the C-30 polyisoprene precursor to cholesterol. In recent years, the search for inhibitors of squalene synthase for use as antihypercholesterolemic agents has intensified. The focus on this enzymatic transformation is due to the unique location of squalene synthase at the first step committed to sterols in the isoprene pathway. Selective inhibitors of this enzyme are expected to block cholesterol biosynthesis, without having deleterious effects on the branch pathways of isoprene biosynthesis. Potent inhibitors of squalene synthase have been discovered utilizing three of the major methods for drug discovery: rational design, synthetic chemical screening and natural products screening. These inhibitors have been shown to be potent and effective cholesterol lowering agents in animal models. This article will review the rationale for squalene synthase as a drug discovery target, recent advances in the biology of squalene synthase, and the progress toward clinically useful inhibitors of this key enzyme.