Background Protein transduction domains (PTDs), a novel structure for carrying various of macromolecules through the blood-brain barrier (BBB), have been receiving great attention in the recent years. Objective In order to provide a reference for the related fields, we summed up the neuroprotective effects and possible mechanisms of TAT-mediated protein transduction domain, which is the most extensively studied PTDs. Content TAT-mediated protein transduction domain is a special structure of human immunodeficiency virus type I (HIV-I). Up to now, it has been fused with erythropoietin (EPO), glial cell line-derived neurotrophic factor (GDNF), Nogo Extracellular Peptide 1-40 (NEP1-40), and Bcl-xL. These fusion proteins could not only pass through the BBB, but also offer neuroprotection for alleviating cerebral ischemia injury with reduced side effects. Most of all, TAT-NR2B9c, a fusion protein of TAT and synapses dense protein-95 (PSD-95), has been proved to be efficient for reducing cerebral infarction by inhibiting neurotoxicity not only in experimental animal, but also in the phase II clinical trial. Trend TAT-mediated protein transduction technique may offer new perspectives for future strategies in stroke therapy.