If the function of vitamin E is that of an antioxidant and the various forms of vitamin E have similar antioxidant activities, then why does RRR-alpha-tocopherol have the highest biologic activity? This chapter describes how interactions by investigators from various scientific disciplines using stable isotopes, molecular biology tools, and sophisticated genetic studies of humans with vitamin E deficiency have led to an understanding of this problem. This chapter provides an overview of (a) studies using deuterated tocopherols that demonstrated that the plasma preference for alpha-tocopherol is dependent on metabolic processes in the liver; (b) the isolation, molecular biology, and function of the alpha-tocopherol transfer protein; and (c) studies that demonstrated that patients who were vitamin E deficient as a result of no known cause had defective alpha-tocopherol transfer protein genes. Finally, we focus on the future--what remains to be learned about the regulation of vitamin E in tissues.