Tissue mast cells are multifunctional immune cells and have been implicated in allergic and inflammatory reactions. However, while the role of allergen binding to surface IgE via the high-affinity Fc epsilon receptor on mast cells is well understood, major questions in mast-cell biology remain to be answered. In particular, it is largely unknown which stimuli lead to the differentiation of human mast cells from their precursor cells and how the maturing cells localize (or home) and acquire effector functions within the microvasculature. A potential solution is suggested by Peter Valent in this viewpoint. The emerging concept is that a single tissue hormone, the ligand of the c-kit tyrosine kinase receptor (CD117), provides a key signal in multiple aspects of mast-cell differentiation and function.