Transplant immunology explores how the immune system interacts with transplanted organs or tissues, focusing on the human leukocyte antigen (HLA) system, alloantigen recognition mechanisms, and the roles of cellular and humoral immune responses in graft rejection and tolerance. The HLA system is fundamental for distinguishing between self and non-self, making it crucial to match HLA types between donor and recipient to minimize rejection risks. Despite this, mismatched non-HLA antigens can still provoke immune responses, complicating transplant outcomes. Alloantigen recognition occurs through three primary pathways: • Direct pathway: Recipient T-cells recognize whole donor HLA molecules presented by donor antigen-presenting cells (APCs). • Indirect pathway: Recipient APCs process donor antigens and present these processed antigens to T-cells. • Semi-direct pathway: Recipient APCs acquire and present whole donor HLA molecules to T-cells. Cellular responses, mainly mediated by T-cells, can lead to acute rejection if not managed with immunosuppressive therapy. B-cells also contribute by producing donor-specific antibodies (DSAbs), which can cause antibody-mediated rejection (AMR). Crossmatching tests, such as complement-dependent cytotoxicity (CDC) and flow cytometry, help detect preformed DSAbs and prevent hyperacute rejection. Advances in molecular HLA typing, including PCR-based methods and next-generation sequencing (NGS), have significantly improved transplant immunology by ensuring precise HLA matching and reducing rejection risks. Virtual crossmatching, which uses solid-phase assays and donor HLA typing, aids in predicting crossmatch results, although it has its limitations. Effective immunosuppressive therapy is crucial for graft longevity, requiring a balance between preventing rejection and minimizing drug-related toxicity and infections. Ongoing research seeks to identify new biomarkers, develop strategies for immune tolerance, and create personalized immunosuppressive regimens to enhance transplant outcomes and patient quality of life.