Current cardiac resynchronization therapy (CRT) devices allow manipulation of the atrioventricular (AV) and interventricular (VV) timings in order to maximize the left ventricular (LV) performance. Multiple echocardiographic and non-echocardiographic methods have been proposed to optimize AV and VV intervals but no consensus has been reached on which methodology should preferably be used. Furthermore, different physiologic conditions, such as rest and exercise, may markedly change LV loading conditions, and therefore an optimal setting determined at rest may be different during exercise. The present article reviews current methodologies to optimize AV and VV interval and discuss why, when and how optimization of these delays may be performed based on current evidence. Moreover, an overview of the results of the multicenter trials on AV and VV intervals optimization is provided.