Background: Alcoholism is common in bipolar disorder and associated with a more severe illness course and poor treatment outcomes. The etiology of the high rate of addiction in bipolar disorder is poorly understood, and few treatment studies have been conducted in this population. Objective: Advances in the neurobiology of addiction inplicate dysregulation of glutamate neurotransmission as critical in the maintenance of dependence and vulnerability to relapse. The current review assessed evidence for (1) glutamate dysregulation in bipolar disorder and (2) the safety and efficacy of glutamatergic agents in studies of alcohol outcomes in patients with and without bipolar disorder. Method: Medline search from 1950 through August 2009. Results: Accumulating evidence for glutamate dysregulation in bipolar disorder is emerging from genetic and magnetic resonance spectroscopy research. To date, patients with comorbid alcohol dependence have been excluded from these studies. Clinical trials of glutamatergic agents as treatments for alcohol dependence have been conducted primarily in subjects without bipolar disorder. Large multicenter trials of the kainate/AMPA antagonist topiramate in non-bipolar alcoholics have reported a significant effect size in reducing drinking. In contrast, the noncompetitive NMDA antagonist memantine failed to reduce drinking under double-blind conditions. In bipolar alcoholics, small open label trials of the glutamate release inhibitors acamprosate and lamotrigine have been positive. Double-blind, placebo-controlled trials of topiramate, acamprosate, and lamotrigine in bipolar alcoholics are currently underway. Conclusion: Agents acting at diverse sites of the glutamate synapse may have promise as novel treatments for comorbid alcohol dependence and bipolar disorder.