Three-dimensional (3D) speckle-tracking echocardiography (3DSTE) is an advanced imaging technique designed for left ventricular (LV) myocardial deformation analysis based on 3D data sets. 3DSTE has the potential to overcome some of the intrinsic limitations of two-dimensional STE (2DSTE) in the assessment of complex LV myocardial mechanics, offering additional deformation parameters (such as area strain) and a comprehensive quantitation of LV geometry and function from a single 3D acquisition. Albeit being a relatively young technique still undergoing technological developments, several experimental studies and clinical investigations have already demonstrated the reliability and feasibility of 3DSTE, as well as several advantages of 3DSTE over 2DSTE. This technique has provided new insights into LV mechanics in several clinical fields, such as the objective assessment of global and regional LV function in ischemic and non-ischemic heart diseases, the evaluation of LV mechanical dyssynchrony, as well as the detection of subclinical cardiac dysfunction in cardiovascular conditions at risk of progression to overt heart failure. However, 3DSTE generally requires patient's breathhold and regular rhythm for enabling an ECG-gated multi-beat 3D acquisition. In addition, the measurements, normal limits and cut-off values pertaining to 3D strain parameters are currently vendor-specific and highly dependent on the 3D ultrasound equipment used. Technological advances with improvement in spatial and temporal resolution and a standardized methodology for obtaining vendor-independent 3D strain measurements are expected in the future for a widespread application of 3DSTE in both clinical and research arenas. The purpose of this review is to summarize currently available data on 3DSTE methodology (feasibility, accuracy and reproducibility), strengths and weaknesses with respect to 2DSTE, as well as the main clinical applications and future research priorities of this emerging technology.