High-throughput sequencing has ushered in a diversity of approaches for identifying genetic variants and understanding genome structure and function. When applied to individuals with rare genetic diseases, these approaches have greatly accelerated gene discovery and patient diagnosis. Over the past decade, exome sequencing has emerged as a comprehensive and cost-effective approach to identify pathogenic variants in the protein-coding regions of the genome. However, for individuals in whom exome-sequencing fails to identify a pathogenic variant, we discuss recent advances that are helping to reduce the diagnostic gap.