Cardiac resynchronization therapy (CRT) improves clinical outcome and survival in advanced heart failure. However, some patients do not respond clinically or show improvement in left ventricular function. Our focus has turned to why such “nonresponders” exist. Follow-up of CRT has led to several explanations, varying by individual patient, and has shown the importance of device programming in CRT in heart failure. The failing heart displays delayed contraction in the ventricle, also referred to as mechanical dyssynchrony. Simply pacing both ventricles simultaneously might not be adequate to optimize systolic function. Individually tailoring the atrioventricular (AV) timing can improve left ventricular filling and cardiac output, and adjusting the interventricular (VV) pacing delay has also been shown to improve hemodynamics. Increasing evidence regarding AV and VV optimization is emerging. This article reviews the current data on optimization, including the physiology, numerous approaches, and current issues.