Bipolar disorder is associated with significant problems in patient management, including misdiagnosis, noncompliance, and comorbid substance use disorders. This article describes strategies for the management of difficult cases, with particular emphasis on the choice of therapeutic agents, such as mood stabilizers and atypical antipsychotics, for optimal control of symptoms and psychosocial interventions for reinforcement of therapeutic interventions. Special attention is given to the relationship between bipolar disorder and substance use disorders.