The National Institute of Mental Health Research Domain Criteria initiative (Insel et al., 2010) calls for a focus on biologically meaningful dimensional constructs in the study of clinical problems. Examples are needed of how Research Domain Criteria constructs can be linked to clinical problems. We examined how two such constructs, threat sensitivity (THT+) and weak inhibitory control (INH–), operationalized using scale measures of fear/fearlessness and inhibition/disinhibition dimensions from established structural models, predicted symptoms of multiple Diagnostic and Statistical Manual of Mental Disorders (4th edition) clinical disorders in 471 community adults. Robust relationships with internalizing disorder symptoms were evident for both trait variables, with THT+ more predictive of fear disorder symptoms and INH– more predictive of distress disorder symptoms. For substance-related problems, prediction was evident only for INH–. Additionally, interactive effects of THT+ and INH– were found for distress disorders, and to a lesser extent, fear disorders. Given their well-established physiological correlates, these dispositional variables represent prime targets for combined psychometric–neurophysiological assessment of broad liabilities to multiple forms of psychopathology.