It is currently estimated that about 20%-30% of adults and 10%-40% of children diagnosed with epilepsy suffer from uncontrolled or poorly controlled seizures, despite optimal medical management. In addition to its huge economic costs, treatment-refractory epilepsy has a widespread impact on patients' health-related quality of life. The present paper focuses on the concepts of refractory and difficult-to-treat seizures and their pharmacological management. Evidence on efficacy and tolerability of rational pharmacotherapy with antiepileptic drug combinations and of non-pharmacological treatment options such as epilepsy surgery, neurostimulation, metabolic treatment and herbal remedies is reviewed. The importance of early identification of the underlying etiology of the specific epilepsy syndrome is emphasized, to inform early prognosis and therapeutic strategies.