SERIES INTRODUCTION to cholesterol require molecular oxygen and could therefore occur only after the evolution of aerobic cells. However, in a fascinating “evolutionary preview” of some of these features, acidophilic bacteria evolved enzymes to anaerobically synthesize cyclic membrane-organizing lipids called hopanoids from squalene (Figure 1). Haines has speculated that hopanoids fill a unique role in acidophile membrane structure, namely, the prevention of inward leakage of protons (4). The structural requirements outlined above demand precision. For example, a molecule almost identical to cholesterol but with a 3α-hydroxyl group instead of a 3β-hydroxyl group (“epicholesterol”) cannot function properly in biological membranes (5). Moreover, the conversion of lanosterol to cholesterol involves a complex series of 18 enzymatic reactions, even though lanosterol is already a cyclic 3β alcohol. In fact, lanosterol and other methylated derivatives cannot substitute for cholesterol in mammalian cell mutants that are auxotrophic for sterols (6). Why? The three methyl groups that are removed from lanosterol to form cholesterol are all on the so-called α-face of the molecule and thus protrude from this otherwise flat surface (Figure 2a). This is particularly true of the axial 14α-methyl group of lanosterol. Bloch and others have suggested that the removal of these three methyl groups allows proper fitting of the ring structure to the fatty acyl chains of membrane phospholipids, particularly those that are saturated (1, 7)(Figure 2b). According to this model, cholesterol optimally binds natural membrane phospholipids, which usually contain a saturated fatty acid at sn-1 and an unsaturated fatty acid at sn-2. In par-