Vital exhaustion has been implicated in the development and progression of cardiovascular disease. In addition, elevated levels of fibrinogen and D-dimer have been associated with an increased risk of cardiovascular disease. Some studies have suggested that fibrinogen and D-dimer are associated with acute, chronic, and perceived stress. In this issue, Kudielka et al examine the relationship between circulating fibrinogen and D-dimer levels and vital exhaustion in a cross-sectional study of middle-aged teachers in Germany, to examine the plausible link between chronic stress and the development of cardiovascular disease. This commentary discusses the limited available evidence of the mechanisms responsible for the association between vital exhaustion and the development of cardiovascular disease and highlights the limitations of previous research and discusses future directions.