Depression is the most frequent psychiatric comorbidity in people with epilepsy (PWE) with lifetime prevalence rates ranging between 30 and 35%. Multifactorial variables play a pathogenic role in the high comorbid occurrence of these two disorders. These variables were critically examined during an international symposium held in Chicago in September 2010, the results of which are presented in two companion manuscripts. The first manuscript summarizes new epidemiologic data highlighting the bidirectional relation between depression and epilepsy and related methodological issues in studying this relationship. An examination of the neurobiologic aspects of primary mood disorders, mood disorders in PWE and pathogenic mechanisms of epilepsy derived from studies in animal models and humans is allowing a better understanding of the complex relation between the two conditions. In the first manuscript, we review data from animal models of epilepsy in which equivalent symptoms of depression and anxiety disorders develop and, conversely, animal models of depression in which the kindling process is facilitated. Data from structural and functional neuroimaging studies in humans provide a further understanding of potential common pathogenic mechanisms operant in depression and epilepsy that may explain their high comorbidity. The negative impact of depression on the control of seizure disorders has been documented in various studies. In this manuscript, these data are reviewed and potential mechanisms explaining this phenomenon are proposed.