Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizures, cognitive impairments, and distinctive EEG patterns. Given its profound impact on patients' quality of life, developing effective pharmacotherapies remains a critical clinical challenge. This review examines FDA-approved medications for LGS (clonazepam, felbamate, lamotrigine, topiramate, rufinamide, clobazam, cannabidiol, and fenfluramine), commonly used off-label antiseizure medications, emerging treatments in clinical trials, and precision therapeutics targeting etiology-specific mechanisms. The literature encompasses randomized controlled trials, observational studies, and expert consensus statements on treatment approaches and challenges. Despite therapeutic advances, most LGS patients lack individualized treatment plans with regular adjustments. Current management requires a multimodal approach integrating pharmacotherapy with other interventions. Future progress depends on improved natural history studies, standardized data collection, advanced preclinical models, innovative trial designs, and addressing healthcare inequities. While emerging precision therapies targeting genetic causes show promise, the field urgently needs better strategies to optimize existing treatments while developing disease-modifying approaches that address both seizures and non-seizure outcomes.