In recent years, the increasing availability of antiseizure medications has not reduced the incidence of drug-resistant epilepsy. Precision medicine offers the potential for mechanism-driven treatments for rare pediatric epilepsies. The concept of precision medicine is not new in the field of epilepsy, as demonstrated by the use of pyridoxine for antiquitin deficiency (pyridoxine-dependent epilepsy) and the ketogenic diet for GLUT1 deficiency syndrome. More recently, preclinical evidence has led to phase 3 clinical trials, such as the use of everolimus to inhibit the mTOR pathway in tuberous sclerosis complex. However, preclinical findings do not always translate into effective treatments, as illustrated by the heterogeneous effects of quinidine in KCNT1-related epilepsy. Currently, an exponential increase in compounds identified at the preclinical level will require clinical trial validation. However, it remains uncertain whether these developments will lead to improved efficacy in drug-resistant epilepsy or have any disease-modifying effects. This article does not explicitly address antisense oligonucleotides or gene therapy.