Rapid cycling, mixed episodes, and atypical bipolar mood disorder each challenge clinical researchers in distinctly different ways. This chapter explores the issues as they relate to study design in general and offers suggestions for study methodology. The Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) definition of mixed episodes requires a period of at least 1 week during which a patient meets full criteria for mania and major depression. Addressing factors related to the specificity of diagnosis and treatment outcome has great potential to improve the prospects for research on mixed episodes. The DSM-IV classifies rapid cycling as a course specifier rather than a subtype of bipolar disorder. Although rapid cycling is associated with relatively poor response to treatment and persistence of higher rates of cycling than non-rapid cycling, bipolar illness, indices such as family history, and age of onset do not separate rapid-cycling from non-rapid-cycling patients.