It is widely accepted that approximately 85% of known disease-causing DNA variants affect the exons and splice junctions, which is about 1% of the whole genome. As a result, Clinical Exome Sequencing is a powerful and highly efficient diagnostic tool to identify disease-causing DNA variants in individuals. In this talk, I will discuss the methodology, validation, reporting, and bioinformatics aspects of clinical exome sequencing. In addition, I will talk about the regulations regarding reporting of incidental findings and the American College of Medical Genetics guidelines. I will include discussion of advantages and disadvantages of the methodology based on examples of positive and negative clinical exome sequencing results.