In this review, we summarize the best available evidence to guide the conduct of adult cardiopulmonary bypass (CPB) to achieve "optimal" perfusion. At the present time, there is considerable controversy relating to appropriate management of physiologic variables during CPB. Low-risk patients tolerate mean arterial blood pressures of 50-60 mm Hg without apparent complications, although limited data suggest that higher-risk patients may benefit from mean arterial blood pressures >70 mm Hg. The optimal hematocrit on CPB has not been defined, with large data-based investigations demonstrating that both severe hemodilution and transfusion of packed red blood cells increase the risk of adverse postoperative outcomes. Oxygen delivery is determined by the pump flow rate and the arterial oxygen content and organ injury may be prevented during more severe hemodilutional anemia by increasing pump flow rates. Furthermore, the optimal temperature during CPB likely varies with physiologic goals, and recent data suggest that aggressive rewarming practices may contribute to neurologic injury. The design of components of the CPB circuit may also influence tissue perfusion and outcomes. Although there are theoretical advantages to centrifugal blood pumps over roller pumps, it has been difficult to demonstrate that the use of centrifugal pumps improves clinical outcomes. Heparin coating of the CPB circuit may attenuate inflammatory and coagulation pathways, but has not been clearly demonstrated to reduce major morbidity and mortality. Similarly, no distinct clinical benefits have been observed when open venous reservoirs have been compared to closed systems. In conclusion, there are currently limited data upon which to confidently make strong recommendations regarding how to conduct optimal CPB. There is a critical need for randomized trials assessing clinically significant outcomes, particularly in high-risk patients.