Cardiac resynchronization therapy is a key non-pharmacological treatment strategy for drug-refractory moderate-to-severe symptomatic heart failure in the presence of compromised left ventricular function and ventricular conduction delay. Because not all patients with conventional criteria benefit from CRT, continuous efforts have been directed toward improving patient selection; in particular, emerging echocardiographic criteria such as regional and global myocardial strains are being investigated to better predict CRT response. In the meantime, growing evidence from large randomized controlled trials (RCTs, REVERSE, and MADIT-CRT) has demonstrated that even mildly symptomatic patients may benefit from CRT. The role of CRT in heart failure patients with narrow QRS, however, remains to be defined in the scheme of larger RCTs (such as EchoCRT) as the ones carried out thus far (RethinQ and ESTEEM-CRT). Important experimental data derived from animal heart failure models are gradually elucidating the complex pathophysiological basis of cardiac dyssynchrony, which involves diffuse alterations from genome to structure. At the same time, technological breakthroughs, such as wireless endocardial cardiac pacing, will render the prospect of delivering CRT more precisely and more effectively, a reality in the near future.