Epilepsy affects millions worldwide, presenting unique challenges in specific populations such as the elderly, children, and patients with comorbidities or drug-resistant forms. Tailored approaches addressing unmet needs in these subgroups are critical to improving outcomes.This research uniquely integrates real-world evidence and detailed case vignettes from the EPI CONNECT project to evaluate the role of cenobamate in managing these complex cases, providing practical insights beyond traditional clinical trials. The article explores the potential of cenobamate, a novel antiseizure medication with dual mechanisms of action, in improving seizure control, simplifying polytherapy, and enhancing tolerability across various subpopulations. Case-based narratives illustrate its practical use in challenging scenarios.Cenobamate offers important advantages for underserved epilepsy populations, including seizure improvement, polypharmacy reduction, and improved adherence and quality of life. This review seeks to bridge current clinical practice with ongoing research efforts, fostering improved personalized treatment approaches and advancing understanding of cenobamate's long-term role in managing difficult-to-treat epilepsy populations. It aims to provide practical guidance for clinicians and to highlight future research directions, encouraging ongoing investigation into long-term efficacy, safety, and personalized care strategies.