Developing countries have the majority of the world’s population and bear the greatest disease burden. The vast majority of those countries want to participate in the clinical research arena with their own data representing their population. The limited resources available in these countries necessitate the design and availability of evidence-based interventions that are efficient and cost-effective. Paradoxically, the lack of appropriately trained researchers, funding sources, and technical facilities limit the conduct of large-scale clinical trials in these countries that can serve as the basis of these interventional strategies. The identification of suitable measures that need minimal resources in terms of cost as well as skilled personnel is therefore an important requirement for these countries to meet the ever-increasing demands and burden put over the healthcare systems of these developing countries. Evidence extrapolated from randomized clinical trials is considered to be at the top of the evidence pyramid. Cluster randomization can offer logistical when delivered to the entire population rather than at the individual level. A cluster-randomized clinical trial allows both the direct as well as the indirect effects of an intervention to be captured and is well-suited for developing countries. In this review, the difference between the clinical trial studies conducted in the developing and the developed countries are delineated by looking at the clinical trial records of the Kingdom Saudi Arabia (KSA) and Egypt as developing countries, and Canada and Germany as developed ones. The pros and cons of conducting clustered clinical trials in the developing countries are then weighed, followed by ethical and methodological considerations that must be taken into account before conducting clustered clinical trials in the developing world. The benefits of using cluster randomization for the design of randomized clinical trials are then analyzed based on the previous observations.