Recent high-quality studies have confirmed the central role of lithium in the treatment of bipolar disorder and have established lithium as the drug of first choice for long-term prophylaxis in this condition. However, several indications for its use in unipolar major depression are also based on sound evidence. This includes lithium augmentation as a main strategy for depressed patients not responding to an antidepressant, lithium prophylaxis for recurrent unipolar depression as an alternative to prophylaxis with an antidepressant, and lithium's unique anti-suicidal properties. Lithium monotherapy, on the other hand, is not established for acute treatment of depression. Lithium therapy should be a core competency of every psychiatrist, enabling the safe use of lithium, to the benefit of our patients.