Cardiac resynchronization therapy (CRT), or biventricular pacing, has become a standard therapeutic modality for patients with symptomatic heart failure (HF), depressed left ventricular (LV) function, and electrical dyssynchrony. Despite the overall success of CRT in improving morbidity and mortality in selected patients with HF, a significant minority demonstrates nonresponse. This review describes the electrical and physiologic rationale for biventricular pacing therapy, summarizes landmark clinical trials assessing CRT efficacy, highlights strategies to optimize the response to CRT, and frames future challenges in the use, delivery, and care of patients undergoing CRT.