Vitamin B6 is an abundant cofactor in aminoacid- and neurotransmitter metabolism. Physiologic availability depends on dietary supply, intact absorption and conversion of pyridoxamine and pyridoxine into the only active cofactor, pyridoxal-5'-phosphate (PLP) in liver. By now we know of four genetic epilepsies with vitamin B6 dependent seizures. Two are caused by reduced synthesis/availability of PLP (Pyridox(am)in-phosphate oxidase (PNPO) deficiency and infantile hypophosphatasia) and two by increased utilization/inactivation (pyridoxine-dependent epilepsy and hyperprolinemia type II). Aside from hyperprolinemia type II these disorders usually present with therapyresistant (myoclonic) seizures in the neonatal period. The EEG findings may range from burst suppression pattern to unspecific slowing or may even be normal. All four disorders can be diagnosed by reliable biomarkers and be confirmed by molecular analysis of the respective genes. While PLP would benefit all four entities, PNPO patients are typically resistant to pyridoxine and need PLP substitution. Especially in neonatal, therapyresistant seizures, these disorders have to be considered early, to prevent irreversible neurologic damage.