The aim of treatment of all patients with epilepsy is the same: a complete remission of seizures with minimal or no adverse events. However, the means to reach that common goal may differ among patients, not only because of differences in their epileptic syndrome or type of seizures within the same syndrome, but also because of a variety of comorbid pathologic entities that are commonly identified in patients with epilepsy. In this article, we discuss some of the complexities inherent in the planning of therapeutic regimens for epilepsy patients. Comorbid conditions, whether intrinsic or extrinsic to the epileptic disorder, must play a paramount role in the choice of the therapeutic regimen for seizure control. We review the impact of psychiatric comorbidities on the quality of life of patients with epilepsy, with special attention to the tight relationship between depression and epilepsy. Yet, despite this close relationship, comorbid depression is more often than not underrecognized and undertreated. Next, we review the impact of antiepileptic drugs (AEDs) on comorbid medical disorders and give clear examples of the potentially deleterious impact of several AEDs on the therapeutic effects of concomitant medications used for their treatment. Clearly, treating epilepsy is not only about controlling seizures.