An epilepsy comorbidity is a condition or disorder that occurs at a frequency greater than chance in a person with epilepsy. Examples of common epilepsy comorbidities are depression, anxiety, and intellectual disability. Epilepsy comorbidities can be quite disabling, sometimes affecting a patient’s quality of life to a greater extent than seizures. Animal models offer the opportunity to explore shared pathophysiological mechanisms, therapeutic options, and consequences of both the epilepsy syndrome and a given comorbidity. In this chapter, depression is used as an example of how animal models can inform translational questions about epilepsy comorbidities.