With modern immunosuppression, the big negative influence that HLA mismatches had for transplant outcomes in the past has become less apparent, especially in short term outcomes. However, long term outcomes still remain suboptimal despite safer and more effective immunosuppressant, and in spite of improvements in transplantation logistics and patients care protocols. Cold ischaemia and its duration are important sources of injury and activation of the innate system in deceased donor transplantation, but it should be not forgotten that cold ischaemia injury and other peri transplant insults are transient events, while the HLA mismatches are there to remain, in particular for class I HLA molecules, continuosly serving as source for allostimulation. Furthermore, the immune response against those HLA mismatches will tend naturally to escalate due to chronic alloantigen persistence and perennial stimulation of the immune system, with the consequent development of the indolent process of chronic rejection. Thus, efforts to offer the best possible matched organ pay out in the long run, through this is not possible in many occasions in clinical transplantation.