Patients with congenital heart defects are a unique population with generally immature immune systems. Fragility in the postoperative period may contribute to surgical site infections (SSIs), a life threatening complication for this population. The need for postoperative antimicrobial prophylaxis for these patients is a standard of care that is indisputable. When choosing an antimicrobial regimen for surgical prophylaxis, consideration should be given to balancing the prevention of nosocomial infections, avoiding emergence of bacterial resistance, and minimizing drug toxicities and cost.