Intestinal intra-epithelial lymphocytes (iIELs) are a major lymphocyte population, reside in close proximity to the intestinal lumen and are conserved throughout vertebrate evolution. iIELs consist of several unique T-cell phenotypes and express both non-rearranged innate immune receptors and rearranged adaptive immune receptors. The ligands for the innate immune receptors on iIELs, such as NKG2D (natural killer-cell receptor), often bind to non-classical MHC class I molecules, such as the human MHC class I-related molecules MICA or MICB. These ligands costimulate T-cell receptor (TCR)-mediated signaling. In most cases, the MHC molecules that bind to the TCR are still unknown. However, recent efforts to understand the MHC molecules that are involved in the development of and antigen recognition by iIELs have revealed several important results. Here, we focus systematically on recent developments in innate immunity and in TCR recognition of different subtypes of iIELs by various MHC molecules.