Hemolysis is a fact in all extracorporeal circuits, as shown in various studies by the increasing levels of plasma-free hemoglobin (PfHb) and decreasing levels of haptoglobin during and after cardiopulmonary bypass (CPB). Beside complete red blood cell (RBC) destruction or hemolysis, RBCs can also be damaged on a sublethal level, resulting in altered rheological properties. Increased levels of free RBC constituents together with an exhaust of their scavengers result in a variety of serious clinical sequela, such as increased systemic and pulmonary vascular resistance, altered coagulation profile, platelet dysfunction, renal tubular damage, and increased mortality. Sublethal RBC damage is characterized by decreased microperfusion and hypoxic RBCs, leading to end organ dysfunction caused by cellular ischemia. Isolated extracorporeal circuit components can be considered non-hemolytic if used according to recommendations, but extracorporeal circuit composition and management during CPB can still be optimized, avoiding cell damaging mechanical forces. Although most RBC destruction in standard CPB remains within the capacity of the endogenous clearing mechanisms, in some cases, levels of PfHb do substantially rise, and precautionary measures need to be taken. Higher degree of hemolysis can be expected in young children, after extensive surgery, and in prolonged support as in patients supported by ventricular assist devices (VADs) or extracorporeal membrane oxygenation (ECMO). These patients are especially susceptible to the toxic influences of unscavenged RBC constituents and the loss of rheologic properties of the RBCs. Considering the high percentage of neurologic and renal sequela in post-cardiotomy patients, all imbalances possibly contributing to these morbidities should be focused on and prevented, if not treated. Considering the severity of the consequences of RBC damage, the high incidence of this complication, and especially the lack of interventional strategies in cases of suspected or confirmed RBC damage, there may be a need for a treatment algorithm for this phenomenon.