Neural activity is crucial for cell survival and fine patterning of neuronal connectivity during neurodevelopment. To investigate the role in vivo of sodium channels (NaCh) in these processes, we generated knockout mice deficient in brain NaChα_II. NaChα_II^−/− mice were morphologically and organogenically indistinguishable from their NaChα^+/− littermates. Notwithstanding, NaChα_II^−/− mice died perinatally with severe hypoxia and massive neuronal apoptosis, notably in the brainstem. Sodium channel currents recorded from cultured neurons of NaChα_II^−/− mice were sharply attenuated. Death appears to arise from severe hypoxia consequent to the brainstem deficiency of NaChα_II. NaChα_II expression is, therefore, redundant for embryonic development but essential for postnatal survival.