Display omitted •TPGS is a PEG/vitamin E based nonionic amphiphile with GRAS status.•Its core–shell micelles remarkably solubilize the hydrophobic drugs.•It improves dispersion stability and circulation half-life of multi-particulate formulations.•It downregulates efflux transporters and re-sensitizes drug resistant tumor cells.•Chemical modification of TPGS have been explored to improve its targetability. α-Tocopheryl polyethylene glycol succinate (vitamin E-TPGS or TPGS) is a nonionic amphiphile synthesized by the esterification of vitamin E succinate. It has been categorized as a safe excipient by US-FDA and EMA. Like other polyethylene glycol (PEG) condensates, TPGS spontaneously forms kinetically stable core–shell micelles (diameter 12–15 nm) and exhibits interesting properties as solubilizing agent, emulsifier, dispersant and gelling agent. Its aggregation behavior can be tuned in association with other amphiphiles and organic additives. These properties have been exploited for developing a variety of vesicular, semisolid and multi-particulate drug formulations. It improves the bioavailability of drugs through permeation enhancement and down-regulation of P-glycoproteins. Multimodal therapeutic platforms have been explored following its chemical modification with recognizable and stimuli-responsive groups. Research in the past two decades has revealed its specific role in mediating the re-sensitization of multi-drug resistant cancer cells. This review describes the physicochemical and biological properties of TPGS relevant to drug delivery applications. We have emphasized on the role of TPGS in improving the bioavailability and targetability of anticancer drugs.