The history of transplantation begins with the legend of St. Cosmas and St. Damian, who in the year 300 performed the first leg transplant on a deacon of Rome. However, it was not until 1953 that the first successful transplant in humans between twins was performed. From then on, advances in the knowledge of the immune response were fundamental to the development of transplant medicine, in particular the understanding of HLA systems and the immune response to foreign organs. Graft rejection occurs when the immune system detects an organ as “foreign,” generating a series of cellular and molecular responses aimed at eliminating it. Immunosuppressive treatment is key to preventing rejection, but it also increases the risk of infections and cancers. Over the decades, immunosuppressants have improved, moving from steroids and azathioprine to cyclosporine, tacrolimus, and others. Treatment is organized into an induction phase and a maintenance phase. The most recent advance includes costimulation blockers, which modulate lymphocyte activation. In addition, xenotransplantation, which involves transplanting organs from genetically modified animals, has shown progress, such as pig kidney and heart transplants in 2022, although with limitations. Despite these advances, transplant rejection remains a problem. The main cause of immunological graft loss is non-ad- herence to immunosuppressive medication, which can account for up to 64% of cases. In ad- dition, physicians sometimes inappropriately adjust immunosuppression. Therefore, although new drugs and techniques are promising, the success of transplants also depends on proper management of immunosuppression and adherence to treatments.