Background The stress-to-disease association has been well-accepted for some time. However, the understanding of how stress exposure contributes to psychological disease progression remains unclear. Objective To test the real-time impact of variable stress exposure on risk-related clinical phenomena and affective disease progression in a high-risk sample of active-duty firefighters. Methods Participants completed weekly diaries reporting stressful event exposure, affect, sleep, and risk-related and healthy behaviors over six-months and were evaluated for lifetime and current psychiatric disease using clinical interviews before and after the sampling period. Results Stress exposure impacted clinical phenomena in differing ways. Major personal events and day-to-day hassles predicted health-impairing shifts in sleep and behavior that were associated with increases in symptoms and psychological distress over the 6-month period. In contrast, highly aversive incidents predicted greater adaptive behaviors that were uniquely predictive of symptom decreases over the six-month period. Conclusion These findings shed new light on stress-to-disease processes, demonstrating how variable stress exposure influences critical shifts in behavior and sleep, contributing to psychological adjustment of firefighters over time. These data suggest practical ways to monitor risk in high-risk samples (e.g., monitoring sleep latency) and offer avenues for further explication of disease processes in real time.