<p>Despite the use of appropriately selected antiseizure medications (ASMs), seizure freedom remains elusive for some patients at each treatment line, and those failing two ASMs are then classified with drug-resistant epilepsy (DRE). Living with long-term uncontrolled epilepsy can lead to discouragement and disillusionment for both people with epilepsy and clinicians. In the context of potential treatment failure, maximizing seizure control while minimizing adverse events becomes even more critical, necessitating continual symptom surveillance and consideration of therapeutic trials of ASMs where appropriate. This requires truly individualized care, and in this pursuit, physicians will encounter the diametrically opposed challenges of overtreatment (or a burdensome drug load) and therapeutic nihilism (caused by missing consideration of treatment possibilities). This paper presents a detailed review of these issues and the influence of patient- and physician-related factors. Diagnostic and treatment strategies include ensuring accurate diagnosis and epilepsy classification for optimization of ASM treatment, considering the risk-to-benefit ratio when choosing treatment, encouraging treatment adherence, considering the initiation of alternative therapies, adjusting concomitant medications when needed, maintaining awareness of variations in patient characteristics, re-framing emotions effectively, and engaging in effective communication with patients and their families. All will have to be undertaken in conjunction with cognitive and psychological approaches. Seizure freedom is an important and worthwhile goal, and patients and families should be aware that increased therapeutic options available today can make seizure freedom possible even in the context of a challenging a priori prognosis or after previous ASM failures.</p>