Background: Many governments especially in the Middle East countries have been promoting premarital medical examinations since the first half of the 20th century. However, the prevalence of inherited disorders and consanguinity remains high Objectives: To explore the process of implementation of premarital care programs and highlight the possible barriers and challenges to program effectiveness in the Middle East countries. Recommendations to add momentum to current health care efforts were also outlined. Methods: Relevant works of literature were retrieved from different journals and web pages. The electronic databases were searched using the key. The review included both Arabic and English literature related to the premarital care program. Results: A review of the effectiveness of premarital screening programs in the Middle East countries indicated that the program did not achieve the stated objectives in discouraging at-risk marriages and lowering genetic disease prevalence except in some countries providing prenatal detection and therapeutic abortion. Scarcity of resources, lack of trained health professionals, lax enforcement of PMS laws, and high prevalence of consanguineous marriage were the major barriers to the successful implementation of premarital screening programs in the Middle East. Knowledge about inherited genetic disorders and the outcome of the diseases is low. Screening timing, access to prenatal detection and abortion, religious beliefs, also have a role in the success of the program. Conclusions: Efforts should be directed to policy advocacy and public education strategies. A life cycle approach to prevention, incorporation of school screening, awareness campaigns, reconsideration of therapeutic abortion are likely to improve the effectiveness of such programs in the Middle Eastern region.