Celiac disease (CD) is a complex small intestinal disorder due to a dysregulated immune response to wheat gliadin and related proteins which leads to a small intestinal enteropathy. It is generally accepted that CD is a T-cell mediated disease, in which, gliadin derived peptides, either in native form or deamidated by tissue transglutaminase, activate lamina propria infiltrating T lymphocytes which release proinflammatory cytokines. Recent studies indicate that gliadin contains also peptides able to activate an innate immune response. In particular, they induce a selective expansion of IEL, particularly TCRgamma/delta+ and CD8+TCR alpha/beta+ lymphocytes bearing the CD94 NK receptor, as well as a strong epithelial expression of MICA molecules which interact with NKG2D receptor expressed on TCRgamma/delta+ and NK cells. Most of the events of innate immune activation events are inhibited by antibodies neutralizing IL-15, thus confirming the key role of this cytokine as a mediator of intestinal mucosa damage induced by ingestion of gliadin. It remains to be established to what extent the ability of gliadin peptides to activate innate immunity relates to other biological properties exerted not only on celiac cells and tissues; the specificity of celiac patients is probably related to their genetic make up.