The role of the Big Five traits in the occupational stressor-strain relationship was investigated among 211 managers. Direct, mediated, and moderated effect models were used to investigate whether the Big Five affect strain directly (independently of stress), indirectly (via stress and coping), or interactively with stress. Personality, stress, coping, and strain variables were measured and analyzed with path analysis and hierarchical regression. The Neuroticism-physical strain relationship was partially mediated by perceived role conflict and substance use, and the Neuroticism-psychological strain relationship was mediated by perceived stress. Extraversion had a direct, positive effect on physical and psychological strain, and there was preliminary support for a moderating role of Conscientiousness in the perceived stressor-strain relationship. Agreeableness and Openness were unrelated to strain.