Emerging data from experimental and clinical studies have shown that right ventricular (RV) apical pacing led to abnormalities of ventricular activation and contraction, and impairment of myocardial perfusion with adverse left ventricular (LV) remodeling, which was associated with increased risk of cardiac morbidity and mortality. As a result, there is a growing interest in searching for methods to minimize unnecessary RV pacing and preserving normal ventricular activation with alternative ventricular pacing sites. The risk of developing heart failure (HF) after RV apical pacing depends on the interactions between patient-specific factors (baseline atrial rhythm, intrinsic atrioventricular and ventricular conduction, LV ejection fraction, and the presence of HF and myocardial infarction) and pacing-related factors (mode of pacing, site of ventricular pacing, paced QRS duration, and percentage and duration of pacing). In patients with intact atrioventricular conduction, atrial-based pacing should be used to avoid unnecessary ventricular pacing. In patients requiring ventricular pacing, the potential benefits of alternate ventricular pacing sites, such as RV or LV septa, or even biventricular pacing in different patient populations remain unclear and warrant further long-term prospective clinical trial evaluations especially in those patients who are at a higher risk of developing HF after RV apical pacing.