It is well established that depression and cardiovascular disease (CVD) commonly accompany each other.^[1] In patients with existing CVD, depression is associated with worse disease outcomes.^[2] However, the potential existence of a causal relationship has eluded our understanding despite over two decades of research.^[3] It remains unclear if depression may contribute to the development and exacerbation of CVD or whether the presence and severity of CVD may favor the development of depression. This question has been studied extensively in the context of coronary heart disease (CHD) and more advanced heart disease, especially heart failure (HF). For example, in patients with HF, elevated depressive symptoms have been shown to predict hospitalization and mortality, independent of established HF biomarkers of adverse outcomes.^[4] Moreover, depressive symptoms that worsen over time in patients with HF have also been found to add further to the risk of these adverse outcomes.^[5,6] To better understand the nature of the association between depression and CVD, studies of the biological and behavioral pathways that are common to both are likely to play a critical role.