A great deal of knowledge has accumulated regarding signal transduction after ligation of MHC class I (MHC-I) molecules. In recent years focus has been given to delineation of the intracellular signal pathways activated after MHC-I ligation. Activation of tyrosine kinases leading to a rise in the intracellular free calcium concentration ([Ca2+]i) is the major initial event occurring after MHC-I ligation of T cells. Curiously, the MHC-I-induced signaling is not dependent upon the cytoplasmic tail of the MHC-I molecule, suggesting that the MHC-I molecule induces intracellular signaling through association with other membrane-embedded molecules. More distal signaling events after MHC-I ligation includes activation of the Jak/Stat pathway leading to Stat-3 activation, and activation of the PI3-kinase leading to JNK activation and apoptosis. This review will sum up what is currently known about signaling induced by ligation of MHC-I.