Lamotrigine (Lamictal) was developed as a result of screening folate antagonists as anticonvulsants. Lamotrigine proved effective in several animal models of epilepsy, was developed as an antiepileptic drug, and was marketed for the adjunctive treatment of partial seizures in the United States in 1995. Initial, postmarketing, open, clinical experience suggested efficacy in a variety of neurologic and psychiatric conditions, coupled with good tolerability (aside from the risk of rash). Later, double-blind, placebo-controlled studies revealed that lamotrigine was useful for some, but not all, of the neurologic and psychiatric conditions reported in open studies. Thus, lamotrigine appeared effective as maintenance treatment for bipolar disorder and was approved for maintenance treatment of bipolar I disorder in 2003. Lamotrigine also appeared to have potential utility in acute bipolar depression, but the magnitude of the effect was too modest to yield consistently superior performance compared with placebo, and hence lamotrigine did not receive approval for the treatment of acute bipolar depression. Similarly, limited data suggested lamotrigine had potential utility in rapid cycling bipolar disorder. Lamotrigine did not appear to be effective as a main intervention in acute mania. Thus, lamotrigine has emerged as an agent that appears to “stabilize mood from below” in the sense that it may maximally impact the depressive component of bipolar disorders.