Massively parallel sequencing has transformed clinical medicine by identifying causal variants underlying rare genetic disorders, often through large gene panels or exome sequencing. While these approaches have enabled key diagnostic and therapeutic insights, a majority of patients with rare diseases still lack a molecular diagnosis. Genome sequencing offers broader variant detection capabilities, including structural and deep intronic variants, with improved coverage uniformity. However, the incremental diagnostic yield and clinical impact of genome sequencing remain uncertain. Through the Broad Center for Mendelian Genomics and the Rare Genomes Project, we analyzed over 8,000 families with suspected monogenic diseases, evaluating genome sequencing’s effectiveness where exome sequencing fell short. Our findings, further tested in an independent clinical cohort, provide insights into the specific advantages of genome sequencing and its potential for improving rare disease diagnosis. This talk will explore the key features that drive successful diagnoses and the broader implications for genomic medicine.