Human alpha-tocopherol transfer protein (alpha-TTP) plays a central role in vitamin E homeostasis: mutations in the protein are a cause of a progressive neurodegenerative disorder known as ataxia with vitamin E deficiency (AVED). Despite normal dietary intake of vitamin E, affected individuals suffer from a relative deficiency of this essential lipophilic antioxidant. Disease-associated mutations in alpha-TTP impair its ability to prevent the degradation and excretion of alpha-T. Recently, we and others solved the crystal structures of alpha-TTP bound to a molecule of (2R, 4'R, 8'R)-alpha-T, which has led to a better understanding of the molecular basis of its biochemical activity. Surprisingly, the ligand was found buried in the hydrophobic core of the protein, completely sequestered from the aqueous milieu. In this chapter, the implications of the structure of alpha-TTP bound to its ligand regarding the mechanism of alpha-T retention are discussed. A comparison to a crystal structure of the apo form of alpha-TTP indicates a possible specific conformational change that allows the entry and exit of the ligand. The effect of known disease-associated point mutations is examined in light of the crystal structure as well as recent biochemical studies. Despite the knowledge gained from these studies, the exact molecular mechanism by which alpha-TTP retains alpha-T remains enigmatic and will likely prove a fruitful area for future research.