Mast cells (MC) are widely distributed throughout different organs with a relative predilection for potential portals of entry into the host. In tissues, MC are generally concentrated around small blood vessels and lymphatics, as well as nerves and glandular tissue. This close association with vascular structures suggests an important interaction between MC and endothelial cells (EC). Tissue MC are known to generate and release a number of mediators including histamine, prostaglandin D2, and leukotrienes that induce vasodilatation and increased vascular permeability. These MC-mediated effects on vessels may enhance responses to tissue injury or infection by facilitating the deposition of plasma components and inflammatory cells into involved sites. Important interactions between MC, EC, and peripheral nerves also occur. MC-derived histamine and possibly other mediators induce axon reflexes in unmyelinated sensory nerves leading to the release of neurotransmitters such as substance P, calcitonin gene-related peptide, and adenine nucleotides. These neurotransmitters exert direct effects on blood vessels, and in some instances, may act as MC stimulators. In vitro studies indicate that MC also affect EC growth and new blood vessel formation. Mast cell-derived heparin has been implicated as an important cofactor in tumor-induced angiogenesis, whereas histamine has been reported to augment human dermal EC growth in culture. The recent identification of a tumor necrosis factor-like peptide in MC and the reported cytostatic effects of TNF on EC suggest that MC may inhibit the proliferation of these cells under certain conditions. Taken together, these observations indicate that the interactions between MC and EC are important in both physiologic and pathologic events.