Previous reports about primary immunodeficiency disorders have shown variations in the frequency and distribution among populations from different ethnic and geographic backgrounds. In this review we describe peculiarities about combined immunodeficiencies (CIDs) in the Middle East. The frequency and type of genetic defects causing CIDs in this region differ in comparison with those in other populations because of the common practice of consanguineous marriage in the Middle East, which results in the relative increase in autosomal recessive diseases. We highlight some of the challenges in the awareness, diagnosis, and therapy of CIDs in the region and the research opportunities, especially those directed toward the identification of novel disease-causing genes.