This chapter provides a comprehensive overview of immune checkpoints in the context of organ transplantation. It begins by introducing the history and current state of organ transplantation, highlighting the crucial role of immunosuppression in allograft survival. The chapter then explores the expression and function of key immune checkpoints, particularly CTLA-4, PD-1, and TIM-3, in various types of organ transplants, including kidney, liver, and hematopoietic stem cell transplantation. For each transplant type, the chapter discusses the relationship between immune checkpoint expression and clinical outcomes, such as acute rejection, graft survival, and graft-versus-host disease. It also explores the association of immune checkpoint gene polymorphisms with transplant success rates. The content covers both animal model studies and clinical research findings to provide a balanced view of the current understanding in the field. The chapter then transitions to discussing the role of belatacept, a CTLA-4 fusion protein, in allograft transplantation. It reviews clinical trials and real-world evidence of belatacept’s efficacy and safety in various organ transplants, with a focus on kidney transplantation. Finally, the chapter addresses the challenging scenario of using immune checkpoint inhibitors for cancer treatment in transplant recipients. It examines the delicate balance between maintaining allograft tolerance and allowing effective anti-tumor immune responses to highlight the risks of graft rejection and the potential benefits of cancer control.