The two important issues affecting recipients of solid organ transplants and of importance to immunologists are (i) sensitization of the recipient to HLA antigens and the resultant humoral immune response leading to the development of anti‐HLA antibodies; and ii) development of robust assays for early detection of humoral rejection post‐transplant. Evidence from several studies clearly indicates that presence of circulating anti‐HLA antibodies especially donor specific leads to early graft loss and high titres of DSA may even lead to hyperacute or accelerated acute rejection. Long‐term graft survival too is adversely affected by the presence of either pre‐ or post‐transplant DSA. HLA matching status of the recipient – donor pair – is an important factor in the modulation of humoral response following transplantation and in a way affects de novo development of DSA. Data collected over the past decade clearly indicate significantly lower level of DSAs in optimally matched donor‐recipient pairs. HLA mismatches especially those on HLA‐DR and HLA‐C loci have wider implications on post‐transplant graft survival. The presence of circulating anti‐HLA antibodies leads to endothelial damage in the newly grafted organ through complement dependent or independent pathways. Although detection of C4d deposition in renal biopsies serves as an important indicator of humoral rejection, its absence does not preclude the presence of DSAs and humoral rejection, and hence, it cannot be relied upon in every case. The emergence of epitope‐based screening for anti‐HLA antibodies on Luminex platform with high degree of sensitivity has revolutionized the screening for anti‐HLA antibodies and DSAs. Studies indicate that humoral response to non‐HLA antigens might also have a detrimental effect on allograft survival. High titres of such circulating antibodies may even lead to hyperacute rejection. Pre‐emptive testing of solid organ recipients, especially kidney transplant recipients for anti‐HLA and non‐HLA antibodies and aggressive post‐transplant monitoring of allograft function to detect DSAs using Luminex‐based tests, is highly recommended.