Cardiac resynchronization therapy is an established treatment modality in heart failure. Though non-response is a serious issue. To address this issue, a good understanding of the electrical activation during underlying intrinsic ventricular activation, biventricular as well as right- and left ventricular pacing is needed. By interpreting the 12-lead electrocardiogram, possible reasons for suboptimal treatment can be identified and addressed. This article reviews the literature on QRS morphology in cardiac resynchronization therapy and its role in optimization of therapy.