Manic-depressive illness is a common psychiatric disorder with complex etiology that likely involves multiple genes and non-genetic influences. The uncertain path to gene discovery has spurred considerable debate over genetic findings and gene-finding strategies. In this article, I review the main findings, with a focus on: (1) putative linked loci on chromosomes 1q31-32, 4p16, 6pter-p24, 10p14, 10q21-26, 12q23-24, 13q31-32, 18p11, 18q21-23, 21q22, 22q11-13, and Xq24-28; and (2) association studies with candidate genes, dynamic mutations, mitochondrial mutations, and chromosomal aberrations. Although no gene has been identified, promising findings are emerging. I then discuss the challenges and opportunities ahead, with special emphasis on gene-finding methods-in particular, questions pertaining to phenotype definition, linkage and association mapping, gene markers, sampling, study population, multigene systems, lessons from other disorders, animal models, and bioinformatics. The progress to date, together with rapid advances in genomics, analytical and computational methods, and bioinformatics, holds promise for new insights into the genetics of manic-depression, in the new millennium.