Mast cells (MC) are best known for their central role in allergic disease but, more recently, MC have also been considered as important elements of the immune system in general. Since the original recognition, more than 10 years ago, that MC may have immunological functions beyond allergic disease, a very long list of physiological and pathological conditions has been accumulated in which MC have been suggested to play important roles. However, definitive evidence for MC functions in areas as important as innate and adaptive immunity, autoimmunity, transplant rejection, vascular diseases, tumour growth, and wound healing are currently mostly lacking. A major hurdle in this field is the lack of a genetically-defined mouse mutant selectively deficient in all MC. The available MC-deficiency models are based on mutations in the pleiotropic growth factor receptor Kit. Kit mutations cause many defects in multiple lineages inside and outside of the immune system, are mostly unavailable on pure genetic backgrounds, and are difficult to combine with other gain or loss of function mutations. We have now generated a new mouse strain that is selective MC-deficient. Cre recombinase (Cre)-mediated MC eradication takes advantage of the genotoxic property of Cre, and does not require Cre-mediated deletion of loxP-flanked genes in MC. These MC-deficient mice are now available for the proposed project on pure C57BL/6 and BALB/c mouse backgrounds. For proof of principle, we are not only demonstrating that MC are absent from these mutants but also provide evidence that these MC-deficient inbred mice behave very differently compared to MC-deficient, Kit-deficient mice in classical assays previously used to suggest in vivo MC functions. Based on these findings, and given the need for conclusive in vivo studies to advance this area of immunology, I propose to develop and lead a research program addressing the in vivo functions of MC in key areas of immunology.