Cholesterol sulfate is quantitatively the most important known sterol sulfate in human plasma, where it is present in a concentration that overlaps that of the other abundant circulating steroid sulfate, dehydroepiandrosterone (DHEA) sulfate. Cholesterol sulfate is generated in the normal epidermis by cholesterol sulfotransferase but then is desulfated in the outer epidermis as part of a 'cholesterol sulfate cycle' that is a powerful regulator of epidermal metabolism and barrier function. It accumulates in the epidermis in the human genetic disorder X-linked ichthyosis. In XLI, cholesterol sulfate levels exceed 10% of total lipid mass (≈1% of total weight). Cholesterol sulfate is a component of cell membranes where it has a stabilizing role, e.g., protecting erythrocytes from osmotic lysis and regulating sperm capacitation. It is present in platelet membranes where it supports platelet adhesion. Cholesterol sulfate can regulate the activity of serine proteases, e.g., those involved in blood clotting, fibrinolysis, and epidermal cell adhesion. Because of its ability to regulate the activity of selective protein kinase C isoforms and modulate the specificity of phosphatidylinositol 3-kinase, cholesterol sulfate is involved in signal transduction.