Voltage-gated sodium channels initiate action potentials in brain neurons, and sodium channel blockers are used in therapy of epilepsy. Mutations in sodium channels are responsible for genetic epilepsy syndromes with a wide range of severity. Generalized Epilepsy with Febrile Seizures Plus (GEFS+) is caused by missense mutations in Na_V1.1 channels, which have variable functional effects on sodium channels expressed in non-neuronal cells, but may primarily cause loss of function when expressed in mice. Complete loss-of-function mutations in Na_V1.1 cause Severe Myoclonic Epilepsy of Infancy (SMEI or Dravet Syndrome), which involves severe, intractable epilepsy and co-morbidities of ataxia, sleep disturbance, and cognitive impairment. Mice with loss-of-function mutations in Na_V1.1 channels have severely impaired sodium currents and action potential firing in hippocampal GABAergic inhibitory neurons without detectable effect on the excitatory pyramidal neurons, which would cause hyperexcitability and contribute to seizures in SMEI. Similarly, sodium currents and action potential firing are impaired in the GABAergic Purkinje neurons in the cerebellum, which likely contributes to ataxia, and in the reticular nucleus of the thalamus and the suprachiasmatic nucleus of the hypothalamus, which likely contribute to circadian rhythm disturbances and sleep disorder. The imbalance between excitatory and inhibitory transmission can be partially corrected by compensatory loss-of-function mutations of Na_V1.6 channels, and thermally induced seizures in these mice can be prevented by drug combinations that enhance GABAergic neurotransmission. Familial Febrile Seizures are also caused by mild loss-of-function mutations in Na_V1.1 channels. We have proposed a unified loss-of-function hypothesis for the spectrum of epilepsy syndromes caused by genetic changes in Na_V1.1 channels: mild impairment predisposes to febrile seizures, intermediate impairment leads to GEFS+ epilepsy, and severe loss of function causes the intractable seizures and co-morbidities of SMEI. Surprisingly, mutations in other sodium channels that cause epilepsy are rare, but Benign Neonatal Infantile Seizures is caused by mutations in Na_V1.2 channels, and mutations in those channels can also lead to more severe epilepsy syndromes. Understanding the molecular and cellular mechanisms that underlie these genetic epilepsies is yielding much information about non-genetic epilepsy syndromes as well.