Organ transplantation has become an established mode of organ function replacement therapy. The improved survival has been the result of better patient selection and care peri-operatively and during long-term follow-up. The survival rates are highly acceptable at five years post transplantation; renal grafts (85%), liver (70%) and heart (65%). The activity of transplantation around the world is related to health expenditure and national income. Organ donation is still an indispensable factor in organ transplantation since humans are the mere possible donors at present. Organization of organ donation should be a national program. It depends on the government support, the religious and cultural acceptance, and education of the public to the importance of transplantation and organ donation. There are common features of organ transplantation in the MESOT world that include inadequate preventive medicine, uneven health infrastructure, poor awareness of the medical community and public at large of the importance of the organ donation and transplantation, high level of ethnicity and poor government support of organ transplantation. In addition, there is lack of team spirit among transplant physicians, lack of planning for organ procurement and transplant centers and lack of effective health insurance. Patients seek commercial transplantation most of the time. Patients on waiting lists for organ transplantation increase with time and there is a considerably growing gap between supply and demand of organs. Living organ donation is the most widely practiced type of donation in the MESOT countries and includes kidney and partial liver. Cadaver organ donation has a great potential in the MESOT world. Nevertheless, this source is still not utilized properly due to the continued debate in the medical community about the concept of brain death and inadequate awareness of the public of the importance of organ donation and transplantation in many countries in this region. There are three dominant and distinctive models for practice of organ donation and transplantation in the region including the Saudi, Iranian and Pakistani models. The Saudi model includes the presence of a national organ procurement center as a governmental agency to supervise organ donation and transplantation. The Iranian model consists of renal grafts donation from the living genetically unrelated persons to the benefit of patients with end-stage renal disease. The Pakistani model is an interesting charitable funding model for management of end-stage organ failure in the developing countries. We conclude that organ donation and transplantation are hampered with obstacles in the MESOT countries. Solutions need continuous work on many fronts. Local experiences can be implemented into new improved models that can help overcoming current obstacles.