It is estimated that approximately 85% of human disease mutations are located in protein coding regions, therefore selectively sequencing all protein coding regions (exome) would be cost-effective and an alternative strategy to identify diseases' varaints. In 2009, scientists successfully identified one missense mutation in MYH3 among 4 individuals with Freeman Sheldon syndrome (one autosomal dominant disease) through exome sequencing. Since then, exome sequencing has been widely used to identify disease causative or susceptibility genes in Mendelian disorders and complex diseases. The application of exome sequencing in human diseases were summarized in this review.