Natural killer (NK) cells are large granular lymphocytes of the innate immune system, responsible for direct targeting and killing of both virally infected and transformed cells. Under pathological conditions and during inflammation, NK cells extravasate into the lymph nodes and accumulate at inflammatory or tumor sites. The activation of NK cells depends on an intricate balance between activating and inhibitory signals that determines if a target will be susceptible to NK-mediated lysis. Many experimental evidences indicate that NK cells are also involved in several immunoregulatory processes and have the ability to modulate the adaptive immune responses. Many other important aspects about NK cell biology are emerging in these last years. The aim of this review is to elucidate the role of NK cells in tumor angiogenesis and their interaction with mast cells. In fact, it has been observed that NK cells produce pro-angiogenic factors and participate alone or in cooperation with mast cells to the regulation of angiogenesis in both physiological and pathological conditions including tumors.