Organ transplantation remains the only hope for patients in end stage organ failure when no other medication can help. Acceptance of grafts entails a complex biology, cells and molecules functioning, signaling reactions, and legend receptor interactions and needs to be understood to increase the life of the graft and provide patients a disease free life. Computational immunology is helping in the understanding of graft acceptance biology and is a hope for the patients undergoing end stage organ failure. In this chapter, we discuss the application of computational immunology in understanding and enhancing current applications in organ transplantation.