Cholesterol and its relatives possessing the 1, 2-cyclopentanoperhydrophenanthrene ring system (Figure 1) form the sterolome, which comprises a chemical library of more than 1000 natural products found in all forms of eukaryotes and some prokaryotes that serve a myriad of biological functions. 1, 2 The structural and stereochemical commonality of these compounds derive in large part from the action of oxidosqualene synthases (formerly cyclases) that generate the parent sterol frame. In their 1985 Nobel lecture, Brown and Goldstein stated that “cholesterol is the most highly decorated small molecule in biology”, a comment supported by the many Nobel prizes awarded to individuals who devoted a large part of their lives to research one or more aspects of the chemistry and chemical biology of sterols, their metabolites, or other isoprenoids. 2, 3 The first known sterol, cholesterol, was discovered by French chemists as a crystalline component of human gallstones over 230 years ago. In 1789, Francois Poulletier de La Salle observed an alcohol-soluble portion of bile stones, which 10 years later was reported by De Fourcroy to be identical to a waxy material in the fat of putrefied corpses referred to as adipocire. 4 Shortly thereafter, Michel Chevreul established that the crystalline component of bile stones, which gave a melting point of 137 C (accepted mp for cholesterol is 149 C), was distinct from adipocire or that of another waxy material from whale, spermaceti (their mp ranged 44À68 C), and named it “cholesterine” from two Greek words: chole, meaning bile and stereos, meaning solid. 4, 5 In English-speaking countries, the name cholesterin was replaced with cholesterol after recognition that the substance was as a secondary alcohol. The correct formula (C27H45OÀ, which here shows that it has a hydroxyl group although it contains 46 hydrogen atoms) of cholesterol was proposed in 1888 by F. Reinitze, yet it took another 30 years to establish the exact steric representation of the molecule, efforts that led to the Nobel Prizes in chemistry for Wieland (1927) and Windaus (1928). The first connection between cholesterol and human health appeared in 1843 as Vogel showed that cholesterol was present in arterial plaques. 5 Cholesterol was subsequently determined to be widely distributed in the animal kingdom and its isomeric forms, termed “cholesterol bodies” or phytosterol, were shown to frequent the vegetable kingdom. 6 These early attempts at natural product surveys of sterols were based on measurements of melting point, color reaction, optical rotation, and crystalline form. Sterol research changed in the mid-to late 20th century and centered on biomimetic chemistry, tracer work, enzymology, and structure determination using high-field NMR and X-ray diffraction methods, culminating with a broad outline for cholesterol synthesis and the partial or complete purification of all the microsomal-bound enzymes that act on sterols between lanosterol and cholesterol. 7À13 Ergosterol, then cholesterol, was discovered to play multiple cellular roles associated with membrane (bulk role) and signal (sparking) functions, which could be differentiated by structure and amount of compound; 14À17 notably sterols accumulate in cultured plant and animal cells at approximately 3000 fg/cell and in yeast at 20 fg/cell. 18 During