Two-dimensional speckle tracking echocardiography (2D STE) is a novel technique of cardiac imaging for quantifying complex cardiac motion based on frame-to-frame tracking of ultrasonic speckles in gray scale 2D images. Two-dimensional STE is a relatively angle independent technology that can measure global and regional strain, strain rate, displacement, and velocity in longitudinal, radial, and circumferential directions. It can also quantify rotational movements such as rotation, twist, and torsion of the myocardium. Two-dimensional STE has been validated against hemodynamics, tissue Doppler, tagged magnetic resonance imaging, and sonomicrometry studies. Two-dimensional STE has been found clinically useful in the assessment of cardiac systolic and diastolic function as well as providing new insights in deciphering cardiac physiology and mechanics in cardiomyopathies, and identifying early subclinical changes in various pathologies. A large number of studies have evaluated the role of 2D STE in predicting response to cardiac resynchronization therapy in patients with severe heart failure. However, the clinical utility of 2D STE in the above mentioned conditions remains controversial because of conflicting reports from different studies. Emerging areas of application include prediction of rejection in heart transplant patients, early detection of cardiotoxicity in patients receiving chemotherapy for cancer, and effect of intracoronary injection of bone marrow stem cells on left ventricular function in patients with acute myocardial infarction. The emerging technique of three-dimensional STE may further extend its clinical usefulness. © 2013, Wiley Periodicals, Inc.