Response to long-term lithium treatment in bipolar disorder appears to be related to the family history of a patient. Conversely, some studies have indicated that treatment response could identify a subtype of bipolar disorder characterized by a stronger role of genetic factors and possibly by major-gene effects. Several groups have now conducted molecular genetic studies in order to identify genes contributing to the etiology of bipolar disorder as well as genes that may influence long-term treatment response. There is limited evidence that the response to mood stabilizers could be individually specific. This chapter focuses on individual treatments, in particular on lithium for which the most data are available. Subsequently, several other studies found an association between prophylactic lithium response and a family history of bipolar disorder. The chapter presents a study of patients with bipolar disorder responsive to lithium in collaboration with the International Group for Study of Lithium (IGSLI).