Sepsis in patients on extracorporeal membrane oxygenation (ECMO) remains a serious complication. Its presence is a poor prognostic marker and increases overall mortality. Adult patients with prolonged duration on ECMO are at high risk of developing sepsis. Ventilator-associated pneumonia and bloodstream infections are the main sources of infection these patients. A strong early suspicion, drawing adequate volume for blood cultures, and early and timely administration of empirical antibiotics can help control the infection and decrease the morbidity and mortality. The diagnostic and the treatment are both challenging. Cardiac patients have increased risk of nosocomial infection while on ECMO, which may be in part due to longer cannulation times, as well as increased likelihood of undergoing major procedures or having an open chest.