Despite the efforts in developing therapeutics for stroke, recombinant tissue plasminogen activator (rtPA) remains the only FDA approved drug for ischemic stroke. Regenerative medicine targeting endogenous growth factors has drawn much interest in the clinical field as it provides potential restoration for the damaged brain tissue without being limited by a narrow therapeutic window. To date, most of the translational studies using regenerative medicines have encountered problems and failures. In this review, we discuss the effects of some trophic factors which include of erythropoietin (EPO), brain derived neurotrophic factor (BDNF), granulocyte-colony stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), epidermal growth factor (EGF) and heparin binding epidermal growth factor (HB-EGF) in experimental ischemic stroke models and elaborate the lost in translation of the candidate growth factors from bench to bedside. Several new methodologies have been developed to overcome the caveats in translational studies. This review highlights the latest bioengineering approaches including the controlled release and delivery of growth factors by hydrogel-based scaffolds and the enhancement of half-life and selectivity of growth factors by a novel approach facilitated by glycosaminoglycans.