Cardiovascular disease (CVD) is the leading cause of death worldwide, and so the search for innovative and accurate biomarkers for guiding prevention, diagnosis, and treatment is a valuable clinical and economic endeavor. Due to a recent findings that the serum concentration of mitochondrial ATP synthase inhibitory factor 1 (IF1) is an independent prognostic factor in patients with coronary heart disease (CHD), we reviewed the role of this protein in myocardial ischemic preconditioning, its correlation to plasma high density lipoprotein (HDL), the predictive potential in patients with CHD, and its interplay with angiogenesis. IF1 has been positively correlated with plasma HDL-cholesterol, and is independently negatively associated with all-cause and CV mortality in patients with CHD. However, this conclusion is prevalently based on limited data, and more research is needed to draw definitive conclusions. IF1 seems to play an additional role in increasing cell vulnerability in oncologic diseases but may also function as modest inhibitor of angiogenesis in physiological conditions. It has been also explored that IF1 may rather act as a modulator of other molecules more significantly involved in angiogenesis, especially apolipoprotein A1 on which the largest effect could be observed. In conclusion, more research is needed to characterize the role of IF1 in patients with CHD.