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The fate of every organ allografting is ‚rejection’ if nothing is done to halt this natural process. The risks of ‘hyperacute’ ‘accelerated acute’ and ‘acute’ rejection have restricted scientists and clinicians over the years in performing organ transplantationwithin ABO blood group matched pairs only. Subsequent to the development in the field of immunosuppression, ABO incompatible transplants have gained momentum to incorporate a significant population of end stage renal disease patients with incompatible blood group donors into the transplant program. However, optimizing the recipient for transplantation and subsequent accommodation with optimal graft function without tilting to the much easier path of rejection is a challenge. Although most of these steps come under the domain of the nephrologist, it is crucial that as the perioperative physician of a very high stake life modifying surgery, the anesthesiologist, surgeons as well as the intensivist should understand the complex process of desensitization, patient preparation and perioperative management for the best outcome. Lack of understanding about a couple of crucial considerations can jeopardize the delicate balance of immunotolerance and can prove catastrophic. The article highlights these considerations important for the perioperative clinicians along with a description of first 20 patients of blood group incompatible renal transplantation at our Institute.