Two-dimensional (2-D) speckle tracking echocardiography (STE) accurately quantifies circumferential strain (S(circ)) and radial strain (S(rad)) in humans and in large and small animals. This study was performed to assess sensitivity of S(circ) and S(rad) to left ventricular (LV) dysfunction in mouse models. We performed 2-D and M-mode echocardiography 1) in 6 mice during superficial and profound isoflurane anesthesia, 2) serially in 12 mice to monitor the development of heart failure induced by transverse aortic constriction (TAC) and in 8 corresponding control mice, and 3) in 26 mice with varying degrees of TAC-induced heart failure and 12 corresponding control mice immediately before euthanasia. Fractional shortening (FS) and LV mass were measured from standard M-mode tracings, whereas S(circ) and S(rad) were derived by STE. Percent fibrosis and myocyte diameters were assessed from whole heart cross-sectional specimens stained by Masson trichrome. Profound isoflurane anesthesia decreased S(circ) (P = 0.027) but not S(rad) (P > 0.05). Mice subjected to TAC showed an immediate and sustained decrease in FS (P = 0.035), S(circ) (P = 0.016), and S(rad) (P = 0.012). S(circ) showed better correlation with FS (r = 0.56 and P < 0.0001) and LV mass (r = 0.42 and P = 0.0003) than S(rad) (r = 0.54 and P < 0.0001 for FS and r = 0.37 and P = 0.014 for LV mass, respectively). Percent fibrosis correlated better with S(circ) (r = 0.46 and P = 0.004) than with S(rad) (r = -0.32 and P = 0.05), whereas myocyte diameter showed similar correlation with both strains (r = 0.45 and r = -0.44, respectively, and P = 0.006 for both). STE correctly identifies LV dysfunction and histological changes in mice and can be used for the serial assessment of cardiac remodeling in murine models.