Fatigue is a common prodromal symptom for various medical conditions, including acute myocardial infarction. Fatigue is also the core component of vital exhaustion, which consists of a specific triad: excessive fatigue, increased irritability, and feelings of demoralization. In this issue of Psychosomatic Medicine, Frestad and Prescott present a meta-analysis of 16 studies, involving 53,337 participants, which found vital exhaustion to be associated with an increased risk of incident coronary heart disease (CHD) and recurrent cardiac events among individuals with established CHD. After discussing methodological limitations of the studies included in this meta-analysis, we describe these findings in terms of a larger genre of risk that is biopsychosocial in origin and tied to two types of tiredness: “calm tiredness” and “tense tiredness.” The former is regenerative, while the latter enhances disease risk. We propose that besides vital exhaustion, other symptoms of negative affect may combine with tiredness to produce increased clinical risk, such as the presence of depressed mood, an inability to relax or recover after work, and symptoms of burnout. We further propose that vital exhaustion can be considered as part of a larger paradigm, ranging from a positive state of vitality to a negative state of exhaustion of vitality. We conclude this editorial by emphasizing the importance of improving vitality and the need to clarify biobehavioral mechanisms that play a role in the association between vital exhaustion and adverse CHD outcomes. New interventions are needed that target reducing exhaustion and improving vitality for individuals at high risk of CHD.