Lithium preparations have been successfully used to treat bipolar disorder (BD), and remain the best established long-term treatment for the disorder. In fact, lithium is a cornerstone of treatment to minimize the risk of recurrences and improve inter-episodic symptomatology. We reviewed the available evidence for the use of lithium in the treatment of BD, including its efficacy, limitations, and potential benefits also in consideration of the different formulations available. We also overviewed salient comparative aspects regarding the long-term alternative use of anticonvulsants, antidepressants, and antipsychotics in BD patients. The available evidence indicates that BD patients should be treated primarily with lithium, combined in some cases with antipsychotics especially in acute treatments, and sometimes, because of intolerance or inefficacy of lithium, with anticonvulsants. The use of adjunctive antidepressants should be limited to episodes of breakthrough depression. Lithium should be offered to the majority of BD patients as initial treatment especially when suicide ideation or behavior is present with adequate information about its long-term benefits and its potential side effects. Many patients can tolerate lithium without concomitant use of antidepressants, which may worsen the course of the illness or antipsychotics, which may cause severe long-term side effects.