To provide an overview of the available high quality evidence-base of studies of adjunctive pharmacologic treatment for acute mania. Double-blind controlled trials with adequate samples (n > 100) were identified through search of PubMed/MEDLINE and computerized abstracts from 2004-2006 meetings of the American Psychiatric Association, International Conference on Bipolar Disorder, and Collegium Internationale Neuro-Psychopharmacolium using key words mania, adjunct, and combination. Placebo-controlled studies with positive results support the adjunctive use of five agents including valproate, olanzapine, risperidone, quetiapine, and haloperidol. Agents with only negative or failed placebo-controlled studies included carbamazepine, gabapentin, lamotrigine, topiramate, oxcarbazepine, and ziprasidone. We found no placebo-controlled study of many commonly used agents including lithium, aripiprazole, and clozapine. No studies explicitly excluded subjects, based on prior treatment with the monotherapy being offered and several studies limited randomization to patients with documented inadequate response to the monotherapy arm. The available placebo-controlled randomized clinical trials support adjunctive therapy combining lithium or valproate with olanzapine, risperidone, haloperidol or quetiapine. The additional increment of antimanic efficacy of these combinations over monotherapy was similar in magnitude to that seen for the same agents as monotherapy in comparison with placebo. These additive benefits enhanced the tolerability of adverse effects sufficiently to allow a higher proportion of subjects receiving combination therapies to complete the studies than monotherapy treated patients. The available data has several shortcomings and the available studies are inadequate to conclusively determine whether combination treatment is more efficacious than monotherapy when used by subjects naive to both treatments. Nevertheless, adjunctive treatment, which combines agents with proven antimanic efficacy, offers an attractive option for patients with acute mania.