Outside of the canonical function of gaseous transport and pH control, red blood cells regulate vascular tone through a variety of mechanisms including modulation of nitric oxide (NO) signaling, ATP release, and interactions with endothelial cells influencing shear stress regulation of endothelial nitric oxide synthase (eNOS). Hemoglobin within the red cell functions as an oxidoreductase, with oxy-hemoglobin oxidizing NO to form inert nitrate, and when deoxygenated, transferring electrons to nitrite to form NO in a process that contributes to hypoxic NO signaling. Key to maintaining a healthy endothelium is the encapsulation of hemoglobin within the red cell membrane, which creates diffusional barriers for NO uptake and oxidation. This functions to slow scavenging of endothelial produced NO by oxyhemoglobin, allowing for diffusion into the vascular smooth muscle cell, where it can signal through its canonical receptor, soluble guanylyl cyclase (sGC). During pathological RBC hemolysis, the RBC diffusional barriers are disrupted. Systems in place to prevent nitric oxide consumption and to promote NO production collapse, leaving the endothelium with a limited ability to vasodilate. This chapter will review how hemoglobin within the red cell modulates NO signaling, how the red cell influences vascular function and hypoxic vasodilation, systems in place to help NO avoid scavenging in a healthy endothelium, and the endothelial dysfunction that results when red cells hemolyze.