Next generation sequencing is revolutionizing rare diseases medicine. The pace of gene discovery and orphan drugs has accelerated since the implementation of this technology. Despite the successes, this implementation also comes with challenges that are different in depending on the setting : developed versus developing countries. Our talk will explore  some aspects of the implementation of Whole Genome Sequencing on both sides of the development threshold.In the first part, we will present the challenge of reducing the time to diagnostic for critically ill pediatric patients using the rapid whole genome sequencing. Genetic diseases are an important cause of hospital admission and death for small infants. Whole Genome Sequencing in a short turnaround time (rapid WGS, rWGS) represents a valuable exploration in critically ill pediatric patients as it can significantly shorten the diagnostic odyssey while allowing to explore SNVs, CNVs, mitochondrial DNA and microsatellite from the same data. We combined a high-throughput NGS platform with cloud-based computing data analysis services to evaluate the feasibility, time to diagnostic, yield, and utility of rWGS in Belgium in 18 trios and 2 duo since February 2020. We also explored the usefulness of the molecular diagnostic. In the second part, we will discuss the challenges of the implementation of the clinical Whole Genome Sequencing in the first 45 patients included in the iHope Program in the DR Congo.