The etiology of psychological differences among those who pursue distinct lines of work have long been of scholarly interest. A prevalent early and continuing assumption is that experiences on the job influence psychological development; contemporary analysts focus on dimensions indicative of mental health. Still, such work-related psychological differences may instead be attributable to selection processes to the extent that individuals can choose, or be selected to, different lines of work, based on their prior characteristics. Whereas much attention has been directed to employment per se as a key determinant of mental health, we consider work status (employed or not) and hours of work, as well as work quality, including both intrinsic and extrinsic dimensions among those who are employed. We also investigate differences in the effects of work experiences on mental health in distinct phases of the work career. Drawing on eleven waves of longitudinal data obtained from a cohort of ninth grade students followed prospectively to age 45–46 (54% female; 73% white), we examine whether key psychological dimensions indicative of mental health (mastery, depressive affect, and self-esteem) change in response to employment and to particular experiences on the job. The findings, based on a fixed-effects modeling strategy, indicate that observed psychological differences related to employment and work quality are not attributable to stable individual proclivities. Evidence suggests that mental health is responsive to changing experiences at work from mid-adolescence to mid-life.