Although lithium remains the preferred treatment of bipolar disorder, only 60 to 80% of patients with the classic presentation have adequate response to this drug. When the response rate to lithium is considered across the entire spectrum of bipolar disorders, this rate probably decreases to 50%. Natural history, illness subtype, and comorbidity are all important general predictors of response to treatment. At present, the only predictors that seem to differentially favor divalproex, and possible, carbamazepine over lithium are mixed states and rapid cycling. An overview of clinical presentations that predict general and differential response to mood stabilizers is provided.