Blood, a complex fluid medium circulating within the vascular network, is essential in maintaining systemic homeostasis by fulfilling the energy needs of various organ systems. Cellular metabolism and tissue viability depend on adequate perfusion driven by cardiac output. Under normal conditions, arterial blood delivers osmolytes, electrolytes, water, nutrients, and gases, with oxygen being the key one, while venous blood transports carbon dioxide and metabolic waste to be eliminated by the liver, kidneys, lungs, and skin as the blood continues its cycle through the arterial capillaries. The vital components that are delivered by the blood must pass through extensive networks of progressively smaller blood vessels and capillaries, where gas and solute exchange take place on a cellular level. Blood also plays a vital role in regulating temperature, initiating clot formation, and fighting infections. Most oxygen molecules are transported directly bound to hemoglobin within red blood cells, while a small portion of oxygen is dissolved in plasma. This chapter explores the fundamental principles of oxygen transport and blood physiology, emphasizing the vital role that blood plays in this process, but will not discuss the lymphatic system, an additional element in fluid hemostasis. It explores the physical and biochemical properties of blood that make it an efficient medium for oxygen delivery and carbon dioxide removal.