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This is a new algorithm for the pharmacotherapy of acute mania developed by the Psychopharmacology Algorithm Project at the Harvard South Shore Program. The authors conducted a literature search in PubMed and reviewed key studies, other algorithms and guidelines, and their references. Treatments were prioritized considering 3 main considerations: 1) effectiveness in treating the current episode, 2) preventing potential future relapses to mania or depression, and 3) minimizing side effects over the short and long term. After accurate diagnosis, managing contributing medical causes including substance misuse, discontinuing antidepressants, and considering the patient’s child-bearing potential, we propose different algorithms for mixed and non-mixed mania in response to the new classification of bipolar mania in the DSM-5. Patients with mixed mania may be treated first with a second generation antipsychotic (SGA) of which the first choice is quetiapine because of adequate efficacy in acute mania but greater efficacy (than other SGAs) for depressive symptoms and episodes in bipolar disorder and evidence of ability to prevent future episodes of depression. For the second choice SGA in mixed mania, aripiprazole and ziprasidone may be preferred over risperidone and olanzapine. Valproate or carbamazepine, and lithium, in that order, may be added to the SGA for unsatisfactory control of symptoms. For non-mixed mania, lithium is the first-line recommendation. Next, an SGA can be added, and again quetiapine is favored because it is the best at treating and preventing depression. If quetiapine is unacceptable, risperidone is the next choice for non-mixed mania because of better efficacy for this mood state. Olanzapine, though almost as effective in acute mania as risperidone in meta-analysis, is not considered a first-line SGA due to its long term side effects, but it could be a second choice SGA. Valproate is a third-line choice for acute non-mixed mania to consider after lithium and one or two SGAs. Its lack of efficacy in recent randomized controlled trials in mania and lack of known effectiveness for preventing future mood episodes result in it having a lower placement in this algorithm than in other guidelines. If the patient, whether mixed or non-mixed is still refractory despite the suggested medication sequences, then depending on what has already been tried, consider valproate, risperidone, olanzapine, haloperidol, and carbamazepine as first-tier, aripiprazole, ziprasidone, and asenapine as second-tier, and clozapine as third-tier because of its weaker evidence base and greater side effects. Electroconvulsive therapy may be considered at any point in the algorithm if there is a history of positive response or intolerance of medications.