ACTH does not affect delivery of cholesterol to mitochondria but results in accumulation of cholesterol in OMM and a corresponding loss of IMM cholesterol. Cholesterol-P450scc complexes then cease to form, and pregnenolone synthesis is suppressed. The cytochrome itself is not affected by this treatment, since even mild mitochondrial disruption, which relieves the barrier to intermembrane transfer of cholesterol, restores steroidogenesis. Cholesterol transport between the mitochondrial membranes thus became recognized as a limiting, hormonally regulated process (4). This view received further support from work with relatively soluble hydroxycholesterol analogs, which can be metabolized to steroids without any activation process. Because such compounds are not constrained by membrane barriers, their turnover to pregnenolone is intrinsically rapid and cannot be further enhanced by ACTH. These findings suggested that intermembrane transfer of cholesterol, the key control point for steroid biosynthesis, requires new synthesis of one or more proteins that become phosphorylated in response to cAMP. In 1983 and in subsequent papers, Orme-Johnson and colleagues identified a set of rapidly degraded 30-kDa mitochondrial phosphoproteins, collectively identified as phosphorylated p30 StAR (pp30)(6). These proteins are derived from a p37 precursor, which is phosphorylated in response to cAMP and is processed in the mitochondria to the pp30 form. Like the putative labile factor required for steroidogenesis, pp30 disappears rapidly after addition of the translational inhibitor cycloheximide (CHX). To explain the very rapid loss of activity in the presence of CHX, Orme-Johnson and colleagues proposed that the p37 protein is only effectively phosphorylated during translation, prior to entry into the inner mitochondria where pp30 is then formed (6). This model predicted that any loss of pp30 through intramitochondrial dephosphorylation could only be restored through a new cycle of synthesis. Later work does not support a role for dephosphorylation of pp30 in the rapid inactivation of cholesterol metabolism when protein synthesis is blocked. Nevertheless, other aspects of p37’s itinerary and fate appear to match Orme-Johnson and colleagues’ early predictions quite closely. The StAR gene, cloned in 1994 by Clark et al.(7), encodes the p37 precursor protein identified by Orme-Johnson and colleagues. The properties of this unusual protein account for many of the anomalous characteristics of mitochondrial cholesterol metabolism. As predicted, StAR increases cholesterol metabolism and carries an N-terminal mitochondrial targeting sequence. StAR is readily converted to a form that lacks the 68 N-terminal amino acids and that corresponds to the previously reported p30 protein ACTH via cAMP and PKA generates pp30. Consistent with earlier biochemical work that had shown pp30 to be regulated by calcium (8) as well as cAMP, StAR also contains consensus sequences for calmodulin-dependent kinases and PKA. As discussed below, the subsequent discovery that human CAH (a disease in which glucocorticoid production is greatly diminished) results from loss-of-function mutations in the StAR gene (9) established the essential role of this protein for normal adrenal steroidogenesis. This pathology is paralleled in StAR-null mice (10).