The clinical manifestations of depression in people with epilepsy (PWE) are pleomorphic, often associated with anxiety symptoms and anxiety disorders. The ongoing debate of whether the clinical presentation of depression in PWE is unique to this neurologic disorder is reviewed. Comorbid depression can impact the recruitment of PWE for pharmacologic trials with antiepileptic drugs (AEDs). Yet, the impact of depression on the response of the seizure disorder to pharmacotherapy with AEDs and its impact on worse adverse events may bias the interpretation of the trial findings, particularly when depressed patients are included in the AED trials. PWE have a greater suicidal risk than the general population. This risk is mediated by multiple factors, and recent data from the FDA have imputed a potential pathogenic role to all AEDs. The recognition of patients at risk is reviewed. Yet, the validity of the FDA data has been questioned, and the status of this controversial question is analyzed. As in the case of epilepsy, depression and pain syndromes have a relatively high comorbidity. The negative impact of depression on pain is reminiscent of that of depression in PWE; furthermore, the high comorbidity may be also associated with the existence of common pathogenic mechanisms. Neurologists and in particular, epileptologists establish the diagnosis of psychogenic non-epileptic seizures (PNES) in whom a comorbid depressive disorder is very often identified. The role of depression in the course of PNES and its treatment are discussed. Scarce data are available on the treatment of depression in PWE. Thus, clinicians have had to adopt data from patients with primary depressive disorders. We outline a consensus strategy on the identification and treatment of depressive disorders in adult and pediatric patients with epilepsy.