Acute and chronic graft rejections as well as tolerance are true representation of the specificity, complexity, sophistication and redundancy of an elegantly and meticulously designed immune system. Thus in order to predict, diagnose and treat (control) graft rejection it is necessary to determine and understand the steps leading to recognition, stimulation, activation, and amplification of the immune system. It is generally accepted that the first steps leading to the initiation of the immune system cascade, leading to graft rejection, is recognition. Recognition is followed by the ligation of a series of adhesion molecules starting with an antigen to its specific T-cell receptor (TCR)/cluster of differentiation (CD) complex, expressed on the surface of the T cell. In order for the activation to proceed additional costimulatory signals, such as ligation of the CD28/B7, CD4/HLA class II and CD/HLA class I antigens are required. During the activation process, the lymphocyte, begins to acquire new CD molecules such as CD25 (IL-2R), CD69, CD71 and HLA-DR. This is accompanied by an increase of cytokines production by the primed T cell. The cytokines are essential for the differentiation, proliferation and amplification of the T-cell The most important of these cytokines is interleukin (IL)- 2, which is essential for activated T-cell proliferation. The complexity and the polymorphic nature of the immune system have necessitated to design agents that inhibit the immune system at different levels. Cyclosporine (CYA) and Tacrolimus (FK) seems to act on the IL-2 by inhibiting its production thus leading to a decrease in the proliferation of the activated lymphocyte. Some earlier reports have indicated that CYA also blocks the receptor for the HLA-DR antigen on T cells. The newly introduced immunosuppressive agent Cellcept (MMF) reduce the proliferation of T cell by inhibiting purine synthesis and by its action on the type II isomer of inosine monophosphate dehydrogenase16,17. Anti-lymphocyte antibodies (ATG) deplete circulating lymphocytes while selective monoclonal antibodies are directed against IL-2 receptor thus reducing the rate of proliferation of activated T cells. Recently antibodies to the CD40/CD40 ligand have been shown to induce long term graft survival with the inhibition of the Th1 cytokines interferon gamma (INF), IL-2 and IL-12 and upregulating the Th2 cytokines IL-4 and IL-1020,21. Lastly graft rejection can be reduced by blockade of the B7/CD28 costimulation pathway with the fusion protein CTLA-4Ig22.