The article discusses the evolving role of first-tier exome sequencing (ES) in medical diagnostics, particularly in the field of nephrology. ES is a powerful tool that allows for the exploration of the molecular bases of Mendelian disorders, which is especially important in nephrology due to the multitude of rare diseases causing chronic kidney disease (CKD). Up to 30% of patients with CKD do not receive a conclusive diagnosis, and ES has been shown to outperform traditional genetic strategies in terms of diagnostic rates. However, the optimal use of ES and its place in the diagnostic process are still debated. Economic evidence is starting to emerge, suggesting that ES-first strategies may be cost-saving. The article emphasizes the importance of choosing the right diagnostic test for each patient and the need for healthcare systems to adapt to the incorporation of early ES. [Extracted from the article]