Mental stress and emotional arousal can act as triggers of acute myocardial infarction and other adverse cardiovascular outcomes. Experimental research examining mechanisms of the adverse interplay between mind and heart has led to the discovery of mental stress-induced cardiac dysfunction or myocardial ischemia (MSIMI). Evidence about the prevalence, clinical significance, and mechanistic bases of MSIMI outlines a wide range of central and peripheral bio-pathologic processes that are associated with emotions and behaviors. MSIMI is recognized as an integrated and intermediate biomarker underpinning the negative mind-heart interplay. Particularly, MSIMI research paves the way toward investigations aiming more specifically at recognizing the susceptibilities of individuals who are prone to respond adversely to the psycho-social-environmental stress. This article reviews recent literature on MSIMI research following the comprehensive review of Strike and Steptoe Eur Heart J 24:690–703, 2003. Further, this article outlines the main steps in the identification of the specific bio-pathologic manifestations of the cardiovascular system to emotional stress. Finally, a speculative description is provided of future directions in better searching for areas that may be critical targets in resolving adverse mind-heart interplays.