In a 61-year-old woman with well controlled arterial hypertension, hypercholesterolemia, and smoke and suffering from recurrent angina pectoris despite angiographically normal epicardial coronary vessels and maximal therapy, the replacement of nitrates with novel antiangina drug ranolazine, after 6-month therapy, induced a complete relief of angina and a relevant rising of the transthoracic Doppler-derived coronary flow reserve (CFR). The present clinical case underlines therefore how in patients with chronic ischemic heart disease without epicardial coronary stenosis ranolazine can induce an improvement till the complete solution of the angina symptoms and a substantial increase of CFR as expression of the enhancement of the microvascular coronary function. The improvement of both symptoms and coronary microvascular function is strictly linked to the mechanism of action of the drug. Ranolazine induces in fact a reduction of the intracellular late sodium current that leads to a reduction of the intracellular calcium concentration thus producing a better myocardial diastolic relaxation process which in its turns enhances the myocardial perfusion. The ranolazine acts therefore as a lusitropic drug that improves the diastolic dysfunction and the segmental ischemia thus affecting one of the first steps of the ischemic cascade.