A precise understanding of the alloimmune risk faced by individual recipients at the time of transplant is an unmet need in transplantation. Although conventional HLA donor-recipient mismatch is too imprecise to fulfil this need, HLA molecular mismatch increases the precision in alloimmune risk assessment by quantifying the difference between donors and recipients at the molecular level. Within each conventional HLA mismatch the number, type, and position of mismatched amino acids create a wide range of HLA molecular mismatches between recipients and donors. Multiple different solid organ transplant groups from across the world have correlated HLA molecular mismatch with transplant outcomes including de novo donor-specific antibody development, antibody-mediated rejection, T-cell-mediated rejection, and allograft survival. All alloimmunity is driven by differences between donors and recipients at the molecular level. HLA molecular mismatch may represent an advancement compared to traditional HLA antigen mismatch as a fast, reproducible, cost-effective way to improve alloimmune risk assessment at the time of transplantation to move the field towards precision medicine.