All relevant guidelines recommend monotherapy as the initial treatment for manic phases of bipolar disorder (BD), with combination therapy reserved for severe cases or as a subsequent choice. However, in routine practice, monotherapy is often not sufficiently effective for acute and/or maintenance therapy. As a consequence, most patients are given combination therapies. An extensive search concerning combination treatment for manic episodes was conducted for relevant international randomized controlled studies, treatment guidelines and comprehensive reviews published since 1980. The scientific literature is sufficiently rich to validate the superiority of combination therapy over monotherapy in the manic phase in terms of efficacy and prevention of relapse; its safety profile is acceptable. Side effects are more frequent with combination therapy as a whole than with monotherapy, and discontinuation rates due to adverse events are higher. Continued administration of antipsychotics after a manic phase is controversial: drug classification, the course of the disease and the predominant polarity should all be considered before treatment is continued. Combinations including olanzapine and asenapine and to a lesser extent risperidone are associated with weight gain, those including quetiapine, haloperidol and asenapine with sedation, and those including aripiprazole with akathisia. This review of literature leads us to suggest that combination therapy including an atypical antipsychotic with lithium or valproate may be considered as a first-line approach. An appropriate algorithm for making decisions about combination treatment needs to be developed and included in future guidelines.