Background This study evaluates the concept of optimizing ventricular pacing in regard to functional cardiac response. Lead implant based on physiologic variables of contractility at various sites was performed in patients with and without congenital heart disease (CHD). Since right ventricular apical pacing may adversely alter contractility and myocellular function, septal and outflow tract pacing have been advocated. However, there are few studies in the young and essentially none in those with CHD. Methods A total of 113 consecutive patients with and without repaired CHD, aged two to 51 (median 16), some with preexisting epicardial pacemakers, underwent transvenous pacemaker implant using standard sensing/pacing indices plus measurements of pressures, QRS, and contractility responses at each of five predefined potential ventricular implant sites: apex, inflow-, low-, mid-, and infundibular/outflow-septal with each patient serving as his/her own control. Implant was at the site of best contractility with active-fixation, low-threshold steroid-eluting leads. Results Measured contractility indices varied up to 31% (mean 12%) between sites per patient. Septal regions (mid-, inflow-, and low-) were associated with the most optimal and right ventricular epicardial showed the worst contractility (P < 0.05) responses. Apex was optimal in some CHD patients. Threshold and sensing were comparable up to 11 years (mean 7) postimplant regardless of septal site. Conclusion There is no single sweet spot for optimal ventricular pacing, and the best implant sites are patient and CHD variable. Current lead designs ensure chronic stability/performance regardless of site. Proactive contractility-guided pacing implant can optimize chronic paced ventricular function.