With the release of new medications into the armamentarium for the treatment of bipolar disorder, clinicians are required to make prudent treatment decisions in light of insufficient research data for patients with a difficult-to-control illness. Increasingly, clinicians are turning toward a combination or adjunctive treatment out of necessity. Many studies suggest effectiveness of add-on agents in patients with mania who are unresponsive to one or more drugs, while only a limited number of controlled trials actually compare one particular combination regimen to another. Despite this lack of data, there has been no lack of advice for the clinician from clinical recommendations in the form of expert treatment guidelines to case reports describing suggestive findings from the off-label use of newer agents. With a particular emphasis on the treatment of mania, this article reviews the clinical data on the individual agents of foreseeable use in combination treatment for bipolar disorder. We suggest beginning with an agent of established effectiveness when combining medications for the treatment of bipolar disorder.