Major histocompatibility complex (MHC) class I molecules control the repertoire and function of CD8 T cells and NK cells, and both cell types are involved in transplant rejection. Understanding the regulatory role of MHC class I molecules is important in the design of better therapies. This review article focuses on molecular aspects of alloreactive recognition of MHC class I molecules by CD8 T cells and NK cells and on the functional activities of CD8 T cells and NK cells in transplant rejection and tolerance.Recent T cell receptor (TCR)-peptide-MHC class I crystal structures and structural and functional analyses of MHC class I interactions with NK cell inhibitory receptors have revealed new insights into molecular aspects of allorecognition of MHC class I molecules by CD8 T cells and NK cells. In functional studies, CD8 T cells and NK cells have been shown to have conditional and model-dependent roles in allograft rejection. NK cells have also been shown to have an unexpected role in tolerance induction in the transplantation setting.Both CD8 and NK cells play diverse roles in graft rejection and tolerance induction. Further understanding of molecular interactions between MHC class I molecules and TCRs or NK receptors is important and highly relevant to transplantation.