High job demands and low job resources may cause job strain and eventually result in burnout. However, previous research has generally ignored the roles of time and self-regulation. This theoretical article synthesizes the literature to propose a multilevel model that delineates how acute job strain translates into enduring and severe job burnout. We integrate self-regulation perspectives in job demands-resources (JD-R) theory to propose that short-term job strain and eventually enduring burnout is the result of consistently high job demands and low job resources - combined with failed self-regulation. The model shows that when employees are confronted with increased job strain, they are more likely to use maladaptive self-regulation strategies, such as coping inflexibility and self-undermining. In addition, when job strain increases, employees are less likely to use adaptive self-regulation strategies, such as job stress recovery and job crafting. It follows that when the job becomes more stressful, stable resources become more important. Organizational resources such as human resource practices and healthy leadership may help employees to regulate their short-term fatigue and avoid enduring burnout. Furthermore, key personal resources like emotional intelligence and proactive personality may help employees to recognize and regulate their fatigue in an effective way. The proposed model of burnout expands JD-R theory and offers important practical implications for the prevention and reduction of burnout.