Studies of personality and problem behaviors may begin with analyses of the problem and develop hypotheses about personality traits that might be relevant; or they may begin with models of personality and explore links to behavior. Because it is well validated and relatively comprehensive, the Five-Factor Model (FFM) of personality lends itself to systematic exploratory studies that may sometimes lead to unanticipated findings. In this article, we review a program of research in a high-risk, disadvantaged population that illustrates the utility of the FFM in understanding health risk behavior. Previous analyses showed that behavior associated with the risk of HIV infection can be predicted from the personality dispositions of Neuroticism and (low) Conscientiousness.