Epilepsy, a disorder characterized by spontaneous, recurrent seizures, is the fourth most common neurological disorder. It is estimated that approximately 1 in 27 individuals will go on to develop epilepsy within their lifetime. Despite this high prevalence, even the most popular treatment options can carry significant side effects in the case of pharmacological approaches, and even irreversible changes in the case of surgical resection. Additionally, these treatment options are often limited in efficacy, leaving 30–40% of all epilepsy patients with uncontrolled seizures [1]. It is estimated that total healthcare costs associated with epilepsy overall exceed $2.7 billion in the United States alone [2].

In addition to the burden of seizures themselves, patients with uncontrolled epilepsy can experience long-term comorbidities such as cognitive deficits, as well as structural changes, and even devastating negative outcomes, including sudden unexplained death in epilepsy (SUDEP). Altogether, there is an immense need to both advance new strategies for intervention to prevent seizures and uncover the mechanisms by which chronic epilepsy can lead to comorbidities.

The cerebellum is a brain region that may not be traditionally associated with epilepsy or seizures, as it is classically considered a predominantly motor control region, but historical and recent work demonstrate that it is a potentially key node in seizure networks. This review highlights recent results showing that targeted manipulations of the cerebellum and its outputs can robustly influence seizures in multiple animal models of epilepsies, and results from both human and animal model work indicating that the cerebellum is influenced by seizures in a manner that has major implications for patients. The necessary next steps for translational approaches are discussed, as well as the need for a better understanding of cerebellar alterations caused by chronic seizures in order to subvert negative outcomes.