Generalized anxiety disorder (GAD) has undergone a series of revisions in its diagnostic criteria that has moved it, nosologically, away from its original affiliation with panic disorder (PD) and closer to major depressive disorder (MDD). This, together with its high comorbidity and putative shared genetic risk with MDD, has brought into question its place in future psychiatric nosology, prompting the planners of Diagnostic and Statistical Manual—V (DSM-V) and International Classification of Diseases—11 (ICD-11) to set up a workgroup tasked to better understand the relationship between GAD and MDD. This review attempts to summarize the extant data to compare GAD and MDD on a series of research validators to explore this relationship. Although insufficient data currently exist for GAD in several key validator classes, tentative conclusions can be drawn on the diagnostic status of GAD in relation to MDD. Although GAD possesses substantial overlap with MDD in the areas of genetics, childhood environment, demographics, and personality traits, this tends to hold true for other anxiety disorders (ADs) as well, with the strongest evidence for PD. Data from life events, personality disorders, biology, comorbidity, and pharmacology are mixed, showing some areas of similarity between GAD and MDD but some clear differences, again with a moderate degree of nonspecificity. Thus, although the bulk of evidence supports a close underlying relationship between them, the relatively nonspecific nature of these findings provides little more reason to question the nosologic validity of GAD in relation to MDD than that of some other anxiety disorders. Depression and Anxiety 25:300–316, 2008. © 2008 Wiley-Liss, Inc.