A bidirectional association between mood disorders and cardiovascular disease has been described; however, the neurobiological mechanisms that underlie this link have not been fully elucidated. The purpose of this review is first to describe some of the important behavioral neurobiological processes that are common to both mood and cardiovascular disorders. Second, this review focuses on the value of conducting research with animal models (primarily rodents) to investigate potential behavioral, physiological, and neural processes involved in the association of mood disorders and cardiovascular disease. In combination with findings from human research, the study of mechanisms underlying mood and cardiovascular regulation using animal models will enhance our understanding of the association of depression and cardiovascular disease, and can promote the development of novel interventions for individuals with these comorbid conditions.