There has been increased attention on job-related stress and burnout experienced by clinicians working with vulnerable and at-risk populations, including effects on personal mental health, therapeutic decision-making, and job effectiveness. Little is known, however, about the job-related stressors and symptoms of burnout experienced by clinical research staff working with similar populations, especially in terms of moral stress they may experience when adherence to scientific procedures appears to conflict with their personal commitment to address the clinical needs of their research participants or role as health care provider. In this national study, 125 frontline research workers conducting clinical research studies with individuals diagnosed with affective and anxiety disorders completed an online survey including measures assessing research work–related moral stress, job burnout, organizational ethics climate, and organizational research support. Results indicated that younger research workers, those whose research work was part of a graduate assistantship, and perceptions of higher participant research risk were associated with higher levels of moral stress and job burnout. Supportive organizational climates were associated with lower levels of moral stress and job burnout. Recommendations for clinical research workers, supervisors, and clinical training directors are discussed.