Cardiopulmonary bypass (CPB) is a vital component of many cardiac surgeries. The priming solution, which fills the CPB circuit, must be carefully formulated to ensure rapid flow rates and minimize the risk of air embolism. Hemodilution refers to the dilution of blood hematocrit, which, while beneficial to a degree, must be managed to prevent adverse effects. Historically, blood was the primary choice for priming to maintain a high hematocrit, but research has since highlighted the advantages of hemodilution. This process offers multiple benefits during CPB, such as reducing blood viscosity, improving flow rates, enhancing oxygen delivery, and lowering clotting risks. It also boosts organ function, particularly the kidneys and liver, due to better perfusion. However, excessive hemodilution can lead to complications like anemia and reduced oxygen delivery, increasing the risk of ischemia in vital organs. To address these risks, hemodilution reduction strategies have been developed, which involve a mix of crystalloids, colloids, and additives that aim to optimize the oxygen-carrying capacity while minimizing hemodilution. Advanced techniques such as autologous blood priming and the use of hemodilution reduction devices, which are tailored to the individual patient’s physiological parameters, represent the forefront of these strategies. Factors like initial hematocrit, body surface area, and the specific surgery being performed play crucial roles in the decision-making process, allowing surgical teams to tailor CPB priming solutions effectively. This chapter explores the evolution, present practices, and anticipated advancements in CPB priming solutions. It highlights the optimization strategies that are essential for reducing the potential complications of excessive hemodilution.