Early diagnosis and treatment vitamin and/or cofactor responsive encephalopathies and seizures is critical for both seizure control and cerebral development and to prevent the kindling of intractable seizures with secondary brain injury. Recognition of these specific disorders is key to their management given their essential requirement for specific cofactors and their reduced responsiveness to standard anticonvulsant therapy. The overall goals of this review are; (1) To provide recognition of the clinical phenotypes of selected treatable metabolic etiologies of early-onset encephalopathies with seizures; (2) To highlight the appropriate diagnostic investigations for each, and (3) To  outline the effective treatment strategies. Each condition will be described followed by an approach to vitamin-responsive infantile-onset seizure management. A list of vitamin/cofactor responsive neurological conditions is provided in Table 1.