Lamotrigine has undergone a remarkable series of systematic studies since 1994 that now establish it as an efficacious, well-tolerated treatment in bipolar disorder. Its efficacy principally addresses both acute and maintenance phase benefits on depressive symptomatology. These benefits have been demonstrated in placebo-controlled studies, rapid cycling patients, bipolar I and II patients and monotherapy as well as in combination therapy, although this has been less well studied. The drug is exceptionally well-tolerated in long-term treatment, although initial dosing requires gradual dosage escalation to avoid the risk of inducing serious rashes with features within the spectrum of Stevens-Johnson syndrome. Administration with valproate requires a slower dosage titration, whereas, as with many drugs, administration with carbamazepine requires a more rapid dosage increase. In contrast to marketed antidepressants, lamotrigine appears not to induce manic or hypo-manic episodes, nor to increase cycling frequency. This combination of properties makes it a first-choice treatment for acute bipolar depression and continuation treatment, especially, but not limited to, prophylaxis against recurrent depression and depressive symptoms. Lamotrigine appears not to have acute antimanic properties. A small number of studies suggest a broader spectrum of efficacy, including in some axis I disorders that are comorbidly associated with bipolar disorder.