Emerging data from several different lines of investigation point to Crohn disease (CD) resulting from a defective innate immune response to commensal and/or pathogenic bacteria encountered in the gastrointestinal tract. Although this defect is, at least in part, genetically determined, mechanistic studies of disease pathogenesis are expected to uncover pathways amenable to pharmacologic intervention to bolster immune responses and ultimately reduce microbe-induced inflammatory responses. One pathway of particular interest is vitamin D-induced innate immune responses. This interest is heightened by the broad consensus among researchers studying vitamin D action that substantial portions of populations throughout the world may be vitamin D insufficient or deficient. The active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], is a hormone that signals through the vitamin D receptor (VDR), a nuclear receptor and ligand-regulated transcription factor. Genome-wide studies of 1,25(OH)2D-regulated gene expression have provided numerous unexpected insights into the broad physiologic functions of vitamin D signaling. Notably, the 1,25(OH)2D-bound VDR is a direct inducer of genes encoding antimicrobial peptides, vanguards of innate immune responses against bacterial infection. 1,25(OH)2D also stimulates transcription of the gene encoding the pattern recognition receptor NOD2. This links vitamin D signaling directly to CD as deficient or absent NOD2 function is strongly linked to the pathogenesis of ileal CD. These findings and others demonstrating that local production of hormonal 1,25(OH)2D is stimulated by pathogen recognition strongly link vitamin D metabolism and signaling to maintenance of innate immune responses to intestinal flora and suggest that vitamin D insufficiency may increase the risk of development of CD.