Recognition of limited overall benefits from lithium in bipolar disorder, with even greater disadvantages in more severe forms of the disease, has spurred interest in alternative therapies. A long history of development of evidence for the utility of valproate has culminated in well-designed, placebo-controlled studies that establish the efficacy of the divalproex form of valproate in acute mania. Generally positive, but as yet not conclusive, studies indicate continued benefits in prophylactic treatment of bipolar disorder. The spectrum of efficacy of valproate is somewhat broader than that of lithium, extending to patients with certain more severe forms of the illness; e.g., mixed manics. Pretreatment plasma GABA activity was positively correlated with magnitude of improvement in manic symptomatology with divalproex. The evidence of comparable clinical benefits for lithium and valproate has stimulated studies that indicate overlapping effects on specific G protein-linked signal transduction for lithium and valproate, but not for carbamazepine. The possibility that additional antiepileptic drugs might have efficacy in bipolar disorder has encouraged early clinical studies with several newer antiepileptic drugs. Preliminary evidence for the efficacy of one of these, lamotrigine, has been presented.