AbstractDespite the introduction of newer antiseizure medications (ASMs) with improved safety profiles over the past several years, rates of treatment‐related intolerable adverse events (AEs) for people with epilepsy have not changed substantially. Tolerability issues can potentially jeopardize optimal dosing and effectiveness, regimen adherence, and treatment retention with these newer medications. Long‐term clinical studies, open‐label extension studies, and postmarketing studies allow flexible dosing and adjustment of concomitant ASMs, which can help clinicians reduce treatment‐related AEs and thus improve the retention and tolerability of these treatments. With newer effective treatments (e.g., lacosamide, eslicarbazepine, perampanel, brivaracetam, and most recently, cenobamate), the risk of AEs may be minimized by proactively adjusting concomitant ASMs that have known pharmacokinetic and/or pharmacodynamic drug interactions. Additional tolerability considerations should be made for specific populations, for example, more determined reductions in concomitant ASMs may be required to improve treatment tolerability in older people, and individuals with more refractory seizures may require higher doses. Strategies to improve the tolerability of effective ASMs further, including earlier add‐on therapy and transition to, or initial, monotherapy should be investigated. Ongoing clinical studies in children and people with generalized tonic–clonic seizures of the most recent ASM addition, cenobamate, will further inform the safety profile of cenobamate and its potential utility as a broad‐spectrum treatment option.