Neuroticism and several other traits have been proposed to confer vulnerability for unipolar mood disorders (UMDs) and anxiety disorders (ADs). However, it is unclear whether the associations of these vulnerabilities with these disorders are attributable to a latent variable common to all vulnerabilities, more narrow latent variables, or both. In addition, some researchers have suggested that neuroticism predicts UMDs, ADs, and substance use disorders (SUDs) with comparable strength, whereas other researchers have hypothesized that neuroticism is more strongly related to UMDs and ADs. We tested hypotheses about the factor structure of several vulnerabilities and the prospective associations of these latent variables with initial onsets of UMDs, ADs, and SUDs during a 3-year period in 547 participants recruited as high school juniors. Although a general neuroticism factor predicted SUDs, it predicted UMDs and ADs more strongly and especially predicted comorbid UMDs and ADs. There was also mixed support for specific associations involving more narrow latent vulnerabilities.