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To analyze the kinase-independent functions of Lyn, mice expressing a catalytically inactive mutant of Lyn were generated and their phenotype compared to Lyn-deficient mice. Disease progression was blunted in Lyn kinase-dead mice indicating a contribution for kinase-independent Lyn functions in restraining autoantibody production, glomerulonephritis, Toll-like receptor signaling, and splenomegaly. Further comparative analyses identified an exclusive role for the kinase-dependent functions of Lyn in regulating B cell receptor signaling, dendritic cell phenotype, and type I interferon production. By contrast, interferon-stimulated gene expression and the regulation of thymic epithelial cell development and T cell selection are previously unidentified, exclusively kinase-independent functions for Lyn. 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