Although cardiac resynchronization therapy (CRT) has been established as an important treatment modality for heart failure patients, at least one third of CRT recipients do not respond to this therapy or derive minimal benefit from it. The impact of the site of left ventricular (LV) pacing on outcome after CRT has been examined extensively. Initial studies suggested benefit of posterior or lateral sites but subsequent work has yielded conflicting results. There also remain conflicting results of apical vs basal pacing sites. Avoiding LV lead placement at sites of transmural scar is however a viable strategy. In addition, The TARGET and STARTER trials, 2 independent, randomized, prospective studies, have demonstrated that targeting LV lead placement to sites of latest LV mechanical activation as defined by speckle tracking echocardiography remains the most promising method to improve clinical outcome after CRT.