The neurotrophins (NTs) nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and NT-4/5 are proteins that regulate cell proliferation, differentiation, and survival in both the developing and mature central nervous system (CNS) by binding to two receptor classes, Trk receptors and p75 NTR. Motivated by the broad growth- and survival-promoting effects of these proteins, numerous studies have attempted to use exogenous NTs to prevent the death of cells that are associated with neurological disease or promote the regeneration of severed axons caused by mechanical injury. Indeed, such neurotrophic effects have been repeatedly demonstrated in animal models of stroke, nerve injury, and neurodegenerative disease. However, limitations, including the short biological half-lives and poor blood-brain permeability of these proteins, prevent routine application from treating human disease. In this report, we reviewed evidence for the neuroprotective efficacy of NTs in animal models, highlighting outstanding technical challenges and discussing more recent attempts to harness the neuroprotective capacity of endogenous NTs using small molecule inducers and cell transplantation.