||The pharmacological management of bipolar disorder encompasses the acute treatment of mood episodes, the continuation phase after initial response, and the longer term prevention of recurrences. Lithium salts have been the first treatment in the modern era in this field, and still represent the gold standard for the various phases of bipolar disorder 60 years after their introduction in the treatment of mania. Alternatives to lithium have been investigated, often following serendipitous observations. Classical neuroleptics and antidepressants have long been used for the treatment of mania and bipolar depression, respectively, even if relevant controlled trials have been rare. Treatment of acute episodes with antidepressants or neuroleptics has been associated with switch into the opposite phase and with cycle acceleration. After the first description of the effects of valproate in the 1960s, several other anticonvulsants have demonstrated antimanic, antidepressant and mood stabilizing properties in bipolar patients. Several second-generation antipsychotics have already been approved by regulatory authorities from different countries for the acute treatment of mania. On the other hand, acute treatment of bipolar depression has long represented a difficult task, even though current trials of various agents are promising. Controlled trials of prophylactic efficacy of bipolar recurrences are difficult and expensive. The duration of a drug in the market has markedly influenced this field. Discrepancies in the definitions of treatment phases reflect the difficulties of long-term studies. Current trials are designed to investigate maintenance effect of treatments after initial response without a clear separation between prevention of relapse and prevention of recurrence. Long-term outcome can perhaps be investigated by naturalistic studies alone, as effectiveness and efficiency are not addressed by controlled trials. Moreover, bipolar disorder often requires combined treatments. Additional issues can be addressed by naturalistic studies alone, including the potential development of resistance after prolonged treatment or after discontinuation of prophylaxis, and the potential poorer outcome when there is a delay in starting prophylaxis or in the presence of atypical features. Observations from specialized facilities support a potential effect of lithium against the otherwise increased mortality of bipolar patients, especially due to suicide. No similar evidence is available regarding currently prescribed alternatives to lithium.