High recurrence rates, chronicity and severity as well as high incidence rates of therapy refractory of bipolar disorder, different clinical manifestations of episodes, and psychiatric comorbidities demand combined drug treatment strategies. Polypharmacy is reported in more than 40 % of bipolar in- and out patients. The aim of this paper is to evaluate the incidence of combined mood stabilizer prescriptions and to delineate preclinical and clinical rationales for these treatment options. Over the last decade frequency of combination therapies with 2 or more anticonvulsants increased from 4.5 to more than 12 %. On the background of the dynamic complexity and being aware of potential side effects of such therapy paradigms, the authors provide a rationale for a thoughtful anticonvulsant combination therapy, considering the preclinical findings from epilepsy research, and clinical trials in bipolar disorder.