Vitamin E is present in plants in 8 different forms with essentially equal antioxidant potential (α-, β-, γ-, δ-tocopherol/tocotrienols); nevertheless, in higher organisms only α-tocopherol is preferentially retained suggesting a specific evolutionary reason for the selective uptake of this analogue. In the last 20 years, the route of the tocopherols from the diet into the body has been clarified and the proteins involved in the uptake and selective retention of α-tocopherol discovered. Cellular functions of the tocopherols that are independent of their antioxidant/radical scavenging abilities have been characterized in recent years. Vitamin E inhibits protein kinase C (PKC), protein kinase B (PKB), tyrosine kinases, 5-lipoxygenase and phospholipase A2 and activates protein phosphatase 2A, and diacylglycerol kinase. A growing number of genes are modulated by the tocopherols at the transcriptional level. The tocopherols also inhibit cell proliferation, platelet aggregation, monocyte adhesion and the differentiation of hippocampus neurons. These effects are unrelated to the antioxidant activity of vitamin E, and possibly reflect specific interactions of each of the tocopherols analogues with enzymes, structural proteins, lipids and transcription factors. Recently, several novel tocopherol binding proteins have been cloned, that may mediate the non-antioxidant signaling and cellular functions of vitamin E and its correct intracellular distribution. In the present review, it is suggested that the main physiological purpose of the α-tocopherol salvage pathway is to maintain a high and continuous plasma concentration of α-tocopherol, via the selective enrichment of VLDL with α-tocopherol. This in turn allows to achieve higher levels of α-tocopherol in the central and peripheral nervous system and in the trophoblasts of the placenta, which are the two tissues mainly affected by vitamin E deficiency. At the molecular level, the non-antioxidant activities associated with each tocopherol analogue may represent the main biological reason for the selective retention of only α-tocopherol in the body, or vice versa, for the metabolic conversion and consequent elimination of the β-, γ-, and δ-tocopherols.