: Several lines of clinical, genetic, and pharmacological evidence point to an association between bipolar and psychotic disorders. The goals of maintenance and prophylactic treatment of bipolar disorder include the prevention of new episodes and the improvement of social, family, and occupational functioning. This goal can be mainly achieved by using long-term adequate pharmacological treatment that is tolerable to patients. Among mood-stabilizers, the main drugs used for such treatment, the role of atypical antipsychotics has greatly increased in recent years. Lithium still remains the drug that has produced the most convincing evidence of prophylactic action and has undergone the longest periods of observation. There has also been good confirmation for the maintenance efficacy of such anticonvulsant drugs as carbamazepine, valproate, and lamotrigine, the last having the strongest properties for prophylaxis of depressive episodes. The case for the usefulness of second-generation antipsychotic drugs in the long-term treatment of bipolar disorder has been rapidly accumulating. Based on controlled trials, the best evidence for maintenance efficacy exists for olanzapine. The vast majority of patients with bipolar illness experience inadequate response to monotherapy with mood-stabilizing drugs during long-term treatment. Some issues connected with polypharmacy targeting optimal maintenance results are discussed. In addition, the long-term management and the role of antidepressants in treatment of non-bipolar I illness is also briefly described.