Neuronal cell death and its regulation have been extensively studied as an essential process of both neurodevelopment and neurodegenerative conditions. However it is not clear how circulating hormones influence such processes. Therefore we aimed to determine whether the anti-obesity hormone leptin could promote the survival of murine central and peripheral neurons in vitro. Thus we established primary neuronal cultures of dopaminergic midbrain neurons and trigeminal sensory neurons and induced cell death via either toxic insult or growth factor withdrawal. We demonstrate that leptin promotes the survival of developing peripheral and central neurons via activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3-kinase)/Akt/nuclear factor kappa B (NF-kappaB) -dependent signaling cascades. Specifically, leptin protects dopaminergic midbrain neurons from the apoptotic stimuli, tumor necrosis factor alpha (TNF-alpha) and 6-hydroxydopamine (6-OHDA). In addition, it promotes the survival of postnatal, but not embryonic, trigeminal sensory neurons following neurotrophin withdrawal. Our data reveal a novel neuroprotective role for leptin in the peripheral nervous system while expanding on the known anti-apoptotic role of leptin in the CNS. These findings have important implications for our understanding of neuronal viability.