Attempts to map susceptibility genes for bipolar disorder have been complicated by genetic complexity of the illness and, above all by heterogeneity. This paper reviews the genetic research of bipolar disorder aiming to reduce the heterogeneity by focusing on definite responders to long-term lithium treatment. The available evidence strongly suggests that lithium-responsive bipolar disorder is the core bipolar phenotype, characterized by a more prominent role of genetic factors. Responders to lithium have typically a family history of bipolar disorder (often responsive to lithium). They differ from responders to other mood stabilizing drugs in their family histories as well as in other clinical characteristics. The molecular genetic investigations of bipolar disorder responsive to lithium indicate possibly several loci linked to and/or associated with the illness. A combination of research strategies employing multiple methods such as linkage, association, and gene-expression studies will be needed to clarify which of these represent true susceptibility loci.