This chapter explores the critical aspects of monitoring and maintaining adequate perfusion during cardiopulmonary bypass (CPB), an essential process in ensuring patient safety and optimal outcomes in cardiac surgery. CPB requires a delicate balance between the body’s oxygen supply and demand, with particular attention to the heart, brain, kidneys, liver, lungs, and gastrointestinal tract. Key factors influencing this equilibrium include CPB flow, temperature management, hematocrit/hemoglobin levels, and oxygen delivery. The chapter delves into the complexities of these variables, such as the choice between pulsatile and non-pulsatile flow, the impact of systemic hypothermia on metabolic rates, and the benefits and risks associated with hemodilution. It also discusses the challenges in defining and achieving “optimal” perfusion, given the continuum from inadequate to adequate to optimal states. The chapter further examines various monitoring techniques to assess the adequacy of perfusion during CPB. These include measuring mean arterial pressure, central venous pressure, cerebral oximetry using near-infrared spectroscopy, urine output as a surrogate for renal perfusion, in-line venous oxygen saturation, the carbon dioxide gap, and lactate levels. Each method offers insights into different aspects of systemic and organ-specific perfusion, highlighting the complexity of managing CPB. The chapter emphasizes that while specific end-organ monitoring remains challenging, understanding and interpreting a combination of these surrogate markers are crucial for making informed clinical decisions. The overarching goal is to tailor interventions to individual patient needs, considering the interplay of various physiological variables and the limitations inherent in the available monitoring technologies. The chapter concludes with clinical pearls, summarizing key takeaways and guiding principles for optimizing patient care during CPB.