In this report, we describe the results of the first genome-wide linkage survey for genetic loci that influence the development of unipolar Mood Disorders in 81 families identified by individuals with Recurrent, Early-Onset, Major Depressive Disorder (RE-MDD). Model-free linkage analysis was performed using genotypes for 392 highly informative polymorphisms with an average spacing of 9 cM. The highest maximum LOD score observed, 8.19 (genome-wide adjusted P ≪ 0.0001), occurred for Recurrent Major Depressive Disorder (R-MDD) at D2S2321 (205 cM), located 121 kb proximal to CREB1. Nineteen chromosomal regions contained linkage peaks that reached genome-wide statistical significance (genome-wide adjusted P < 0.05) and ten of these were “highly significant” (adjusted P < 0.001). Six of the 19 linkage peaks were revealed only when the analysis included covariates to control for the effects of sex and linkage to CREB1. Sex-specific susceptibility loci were common and preferentially affected the vulnerability of women to developing unipolar Mood Disorders. Five loci revealed evidence of interaction with the CREB1 locus in determining susceptibility (epistasis). A systematic candidate gene analysis is presented and potential overlaps of the linkage regions for unipolar Mood Disorders with those reported for other psychiatric disorders are discussed. The findings suggest that genes whose products participate in cellular signaling pathways that converge on CREB, as well as the target genes whose expression they regulate, may also harbor alleles that affect the development of Mood Disorders and related conditions. © 2003 Wiley-Liss, Inc.