This presentation will outline the discovery, using structure based drug design, of potent and selective GSK-3 inhibitors that only modulate a subset of the enzyme′s effects with favorable consequences for safety. These compounds preferentially inhibit GSK-3 tyrosine autophosphorylation (pTYR) over GSK-3 Ser/Thr kinase activity against substrates such as β-catenin. The inhibition of GSK-3 p-Tyr results in partial inhibition of enzymic activity (∼90%) resulting in selective downstream effects. Using E16 hippocampal neurons cultured in vitro, we demonstrate that inhibition of GSK-3 at levels that selectively affect TYR residue autophosphorylation, results in increased branching of both axons and dendrites and a reduction in the levels of phospho-CRMP-2. These findings suggest that such inhibitors may provide benefit in neuroregeneration following injury. Having demonstrated that partial inhibition of GSK-3 at p-TYR concentrations correlates with mechanisms that are beneficial to neurorepair, we examine the effects of our inhibitors in an MCAO model of stroke.