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Functional mitral regurgitation (FMR) is a common finding in patients with ischemic or nonischemic dilated cardiomyopathy as a complication of left ventricular (LV) dysfunction and remodeling associated with a fibrotic remodeling response of mitral leaflets to abnormal valvular loading. Although mitral valve tenting is the main determinant of FMR, clinical and experimental observations suggest that intraventricular delay could be a potential co-determinant of FMR. LV dyssynchrony can potentially contribute to FMR by several mechanisms, such as creating an uncoordinated regional LV mechanical activation in segments supporting the papillary muscles, determining diastolic mitral regurgitation, reducing the sphincteric function of the mitral annulus, and decreasing the efficiency of LV contraction and closing forces. Cardiac resynchronization therapy has been demonstrated to reduce FMR with correction of some of the underlying pathophysiological mechanisms. The present review article focuses on the role of mechanical dyssynchrony as a pathophysiological determinant of FMR, and on the potential role of cardiac resynchronization therapy as a therapeutic option for treatment of FMR in patients with severe heart failure and advanced LV dysfunction.