Lowering of standard serum lithium levels to 0.5–0.8 mmol/l has led to a marked reduction of side effects. Safety is increased through temporary discontinuation or dosage reduction of lithium in special risk situations. In unipolar but not in bipolar patients maintenance treatment with antidepressants is a valid alternative to lithium, and treatment choice may be determined by individual tolerance. Carbamazepine and valproate are worth trying in bipolar patients not responding to or not tolerating lithium. General principles for long-term preventive therapy are discussed.