Epilepsy is a serious neurological disease with substantial genetic contribution. We have recently made major advances in understanding the genetics and etiology of the epilepsies. However, current antiepileptic drugs are ineffective in nearly one third of patients. Most of these drugs were developed without knowledge of the underlying causes of the epilepsy to be treated; thus, it seems reasonable to assume that further improvements require a deeper understanding of epilepsy pathophysiology. Although once the rate-limiting step, gene discovery is now occurring at an unprecedented rapid rate, especially in the epileptic encephalopathies. However, to place these genetic findings in a biological context and discover treatment options for patients, we must focus on developing an efficient framework for functional evaluation of the mutations that cause epilepsy. In this review, we discuss guidelines for gene discovery, emerging functional assays and models, and novel therapeutics to highlight the developing framework of precision medicine in the epilepsies.