Abstract:: At present, treatment options for neurodegenerative conditions are severely limited because of lack of safe producible neuroprotectants able to efficiently cross the blood-brain barrier. Small peptides offer several advantages over protein/growth factor-based therapeutics, since they specifically represent neuroprotective motifs of the parent protein, are low cost and readily producible, and can be easily modified to improve their brain penetrability. We recently identified a novel neurotrophic factor, the S100A4 protein, protecting neurons in brain injury, and designed peptides incorporating neurotrophic motifs of S100A4 which mimicked its beneficial effects in animal models of brain trauma and epilepsy. Our data suggest that S100A4 and its peptide mimetics bind to and exerts its neuroprotective effect via the growth factor family receptors of the ErbB family. The peptides promote neuronal survival following oxidative stress or excitotoxicity and protect primary and immortalized dopaminergic neurons in cell models of Parkinson’s Disease. In contrast to S100A4, they do not affect cell proliferation or motility making them promising aids to specifically increase neuronal survival. Our data link, for the first time, S100 family proteins with the ErbB signalling cascade suggesting a novel mechanism of neuroprotection in brain pathologies, and propose S100A4 mimetics as a therapeutic opportunity for neurodegenerative conditions.