This article explores the roles of monotherapy and drug combinations in finding effective long-term treatment for individual patients with bipolar disorder. While current practice relies heavily on combinations, many bipolar patients can be successfully stabilized if the initial monotherapy is carefully selected according to the patient's clinical characteristics. The data show that (1) unequivocal responders to long-term monotherapies such as lithium, lamotrigine, or atypical neuroleptics each have a very different clinical profile, including clinical presentation and course, comorbidity, and, in particular, family history and (2) bipolar patients who respond very well to a long-term monotherapy have often completely failed on other monotherapies. Combinations appear indicated particularly in bipolar patients who are treatment-resistant to monotherapy, do not tolerate it well, or have not yet exhibited the clinical characteristics needed to choose an effective monotherapy.