Co-morbid depression is common in patients with epilepsy and is often undiagnosed. The manifestation of depression in epilepsy is multifaceted with many interacting neurobiological and psychosocial determinants, including clinical features of epilepsy (seizure frequency, type, foci, or lateralization of foci) and neurochemical or iatrogenic mechanisms. Depression is reported more frequently in patients with temporal lobe epilepsy (TLE) and left-sided foci, although not all studies support this finding. In patients with depression and epilepsy, optimal control of seizures should be attained first and foremost with appropriate anticonvulsant treatments including antiepileptic drugs (AEDs) and vagus nerve stimulation (VNS) therapy. Some anticonvulsant treatments (VNS, valproate, carbamazepine, lamotrigine, and gabapentin) have demonstrated mood improvement in epilepsy patients and may have therapeutic potential for this patient population. When antidepressants are necessary to treat depression in patients with epilepsy, selective serotonin reuptake inhibitors (SSRIs) and multireceptor antidepressants are considered first-line treatments. Electroconvulsive therapy is not contraindicated for treatment-resistant or psychotic depression. Depression must be recognized, diagnosed, and adequately treated in patients with epilepsy.