Mast cells play a critical role in innate immunity, allergy, and autoimmune diseases. The receptor/ligand interactions that mediate mast cell activation are poorly defined. The α2β1 integrin, a receptor for collagens, laminins, decorin, E-cadherin, matrix metalloproteinase-1 (MMP-1), endorepellin, and several viruses, has been implicated in normal developmental, inflammatory, and oncogenic processes. We recently reported that α2 integrin subunit-deficient mice exhibited markedly diminished neutrophil and IL-6 responses during Listeria monocytogenes - and zymosan-induced peritonitis. Peritoneal mast cells require α2β1 integrin expression for activation in response to pathogens, yet the ligand and molecular mechanisms by which the α2β1 integrin induces activation and cytokine secretion remain unknown. We now report that the α2β1 integrin is a novel receptor for multiple collectins and the C1q complement protein. We demonstrate that the α2β1 integrin provides a costimulatory function required for mast cell activation and cytokine secretion. This finding suggests that the α2β1 integrin is not only important for innate immunity but may serve as a critical target for the regulation of autoimmune/allergic disorders.