MICA maps about 46 kb centromeric to the HLA-B locus and encodes a stress-induced cell-surface glycoprotein that is expressed in keratinocytes, fibroblasts, gastrointestinal epithelium and in other cell types. MICA is not associated with β2-microglobulin and does not appear to present peptides. MICA displays a high degree of allelic polymorphism within the non-classical HLA gene loci. The functional significance of these polymorphisms is unknown although certain changes in the amino acid sequence of the protein influence the abnormal expression or the affinity in the interaction with NKG2D, its ligand on the surface of NK, Tγδ and T CD8 lymphocytes, affecting NK-cell activation and T-cell response modulation. NKG2D/MICA interaction has been shown to over-ride the inhibitory signal provided by Killer Inhibitory Receptors (KIR) and/or CD94/NKG2A/B molecules, which sense the presence of HLA-A, -B, -C and – E, respectively, on target cells. MICA-NKG2D complex is also a versatile ligand-receptor pair since NKG2D can act as a primary receptor or costimulatory molecule during immune responses. This dual function of NKG2D molecule depending on determined circumstances is still a matter of controversy. Indeed, many tumors express MICA on their surface and circulating soluble MICA also triggers the downregulation of NKG2D and impair lymphocyte cytotoxicity in tumoral escape, highlighting the therapeutic potential of anti-MICA antibodies to overcome immune suppression and effectuate tumor destruction. MICA is also implicated in organ transplants outcome, as MICA antigens elicit a very powerful antibody response in recipients of organ allograft. NKG2D ligand induction might also participate in the amplification loop that leads to tissue damage during aGVHD. MICA is also an important candidate gene for a number of clinically significant diseases including diabetes, rheumatoid arthritis and other autoimmune diseases. This review highlights the advances and limitations of the studies on MICA gene in several pathologies and critically discusses the most recent findings in this rapidly evolving field.