Blood vessel function is highly modulated by the presence of pro-inflammatory mediators secreted by distinct immune cells. Among them, mast cells (MCs) constitute one of the most important innate immune cell types that can initiate inflammatory reactions and modify vascular permeability. Although it is widely accepted that chemical compound-mediated communication between MCs and endothelial cells occurs and is physiologically relevant, new findings on the role of MCs in the generation of vascular networks in normal and pathological conditions (such as tumor growth) suggest a closer relationship between that immune cell and blood vessel function. In this chapter, we discuss some of the most important cellular and molecular characteristics of normal and intratumoral blood vessels, making emphasis on those alterations related to adhesion molecules and regulators of barrier properties of endothelial cells. Then, evidence showing the participation of MCs and its mediators in the generation of intratumoral blood vessels is presented. Finally, we discuss new anti-angiogenic therapies that have been developed based on the new knowledge about the relationship between immune and endothelial cells.