Comorbidity between ADHD and major depression has been reported from both epidemiologic and clinical studies of both children and adults. Our goal was to assess the validity of the association by reviewing family studies of the two disorders. We examined this issue from a genetic epidemiologic perspective by searching the literature for family studies of ADHD children that had assessed depression in relatives and family studies of depressed children that had assessed ADHD in relatives. Family studies of ADHD, family studies of depression, and one population-based family study strongly support the assertion of a familial link between ADHD and depression. ADHD families with antisocial disorders show the greatest risk for depression. However, in the absence of antisocial disorders, ADHD also imparts a familial risk for depression. ADHD and major depression probably share familial risk factors, and the difference between depressed and nondepressed ADHD patients can be attributed to environmental factors. Depression in an ADHD child should not be routinely dismissed as demoralization secondary to ADHD, and depression in mothers of ADHD children should not always be attributed to the stress of living with an ADHD child. The converse statements are equally valid: ADHD in depressed children may not be secondary to depression, and ADHD in the children of depressed mothers may not be a transactional response to the mother's depression.