Mental and emotional stress can provoke transient ischemia and acute coronary syndrome in vulnerable patients. Furthermore, those patients so provoked are at increased risk for recurrent cardiac events and early death. Viable psychological treatments to improve prognosis exist, and preliminary trials demonstrate their efficacy with regard to short- and long-term outcomes, as well as economic savings. These findings heighten the need for efforts directed toward the complete identification of the differential pathophysiology of mental stress-induced ischemia, with an eye toward development of diagnostic tests and establishment of risk stratification algorithms that can be applied in the clinical setting. Ongoing research in this vein is identifying unique aspects of the brain-heart relationship during mental stress that underlie the cognitive and emotional aspects of mental stress, and the "dow nwind" pathways by which distinct patterns of brain activity during mental stress can provoke otherwise silent myocardial ischemia. This research is making important contributions to the larger clinical goals associated with diagnostic testing, risk stratification, and treatment of patients at risk for mental stress-induced ischemia and poorer prognosis.