Despite an increasing amount of research on work-related stress and burnout, our knowledge on the underlying biological mechanisms remains scarce. So far, biomarkers of work-related stress and burnout have been used to identify the biological stress response. Recently, epigenetics has emerged as the key mechanism by which environment and genetics interact, making it an appealing target biomarker for stress-related phenotypes such as burnout. In the present chapter, we provide an overview of current knowledge on (epi)genetic mechanisms linked to work-related stress and burnout and we discuss their potential contribution to our understanding of these phenomena. Moreover, we try to elucidate the potential translational contribution of (epi)genetics and its significance for clinical practice.