Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more drugs in clinical use than any other foreign compound-metabolizing enzyme in humans. Recently, increasing evidence has been found showing that variants in the CYP3A4 gene have functional significance and--in rare cases--lead to loss of activity, implying tremendous consequences for patients. This review article highlights the functional consequences of all CYP3A4 variants recognized by the Human Cytochrome P450 (CYP) Allele Nomenclature Database.