A transgene insertional mutation in the early 1990s led to the discovery of the mouse Scn8a gene, which encodes one of the most abundant sodium channels involved in generation of action potentials in mammalian neurons. A series of loss-of-function and gain-of-function alleles in the mouse revealed many of the in vivo roles of SCN8A and other gene family members. In 2012, a de novo mutation of SCN8A was identified in a child with Epileptic Encephalopathy, a severe disorder that includes seizure onset in the first year of life, developmental delay and intellectual disability. Overall, de novo sodium channel mutations account for 5% of cases, and more than 150 indivduals with SCN8A mutations have been identified. Functional studies in transfected cells demonstrate that 8/10 mutations cause incomplete channel inactivation or premature activition, both leading to neuronal hyperexcitability. A knock-in mouse model carrying one human mutation is being used to characterize the functional impact on various classes of neurons and in the heart, as well as responses to standard epileptic drugs and novel compounds. The interplay of human and mouse genetics has been essential to our understanding of the role of sodium channel gene mutations in neurological disorders.