Genetic-epidemiological data and linkage studies with chromosomal markers are reviewed from the vantage point of X-linked inheritance. The results overall suggest that a gene predisposing to manic depression (bipolar affective illness) localized on the X-chromosome may exist in a subgroup of bipolar cases. However, in light of conflicting findings and methodological uncertainties in studying a disorder with unclear phenotype and complex inheritance, this issue is not yet closed. Additional research, including new linkage data and extension and re-evaluation of published data, is required to further our understanding of this intriguing hypothesis.