Glucocorticoid-Induced TNFR-Related (GITR) protein belongs to Tumor Necrosis Factor Receptor Superfamily (TNFRSF) and stimulates both the acquired and innate immunity. It is expressed in several cells and tissues, including T and Natural Killer (NK) cells and is activated by its ligand, GITRL, mainly expressed on Antigen Presenting Cells (APCs) and endothelial cells. GITR/GITRL system participates in the development of autoimmune/inflammatory responses and graft vs. host disease and potentiates response to infection and tumors. These effects are due to several concurrent mechanisms including: co-activation of effector T-cells, inhibition of regulatory T (Treg) cells, NK-cell co-activation, activation of macrophages, modulation of DC function and regulation of the extravasation process. In this chapter we describe: 1) the main structural features of GITR and GITRL, 2) the transduction pathways activated by GITR triggering, 3) the effects derived from GITR/GITRL system interaction, considering the interplay between the different cells of the immune system. Moreover, the potential use of GITR/GITRL modulators in disease treatment is discussed.