Background— Cardiac resynchronization therapy (CRT) delivered via left ventricular (LV) endocardial pacing (ENDO-CRT) is associated with improved acute hemodynamic response compared with LV epicardial pacing (EPI-CRT). The role of cardiac anatomy and physiology in this improved response remains controversial. We used computational electrophysiological models to quantify the role of cardiac geometry, tissue anisotropy, and the presence of fast endocardial conduction on myocardial activation during ENDO-CRT and EPI-CRT. Methods and Results— Cardiac activation was simulated using the monodomain tissue excitation model in 2-dimensional (2D) canine and human and 3D canine biventricular models. The latest activation times (LATs) for LV endocardial and biventricular epicardial tissue were calculated (LVLAT and TLAT), as well the percentage decrease in LATs for endocardial (en) versus epicardial (ep) LV pacing (defined as %dLV=100×(LVLAT _ep −LVLAT _en )/LVLAT _ep and %dT=100×(TLAT _ep −TLAT _en )/TLAT _ep , respectively). Normal canine cardiac anatomy is responsible for %dLV and %dT values of 7.4% and 5.5%, respectively. Concentric and eccentric remodeled anatomies resulted in %dT values of 15.6% and 1.3%, respectively. The 3D biventricular-paced canine model resulted in %dLV and %dT values of −7.1% and 1.5%, in contrast to the experimental observations of 16% and 11%, respectively. Adding fast endocardial conduction to this model altered %dLV and %dT to 13.1% and 10.1%, respectively. Conclusions— Our results provide a physiological explanation for improved response to ENDO-CRT. We predict that patients with viable fast-conducting endocardial tissue or distal Purkinje network or both, as well as concentric remodeling, are more likely to benefit from reduced ATs and increased synchrony arising from endocardial pacing.