Nasopharyngeal carcinoma (NPC), as a member of head and neck squamous cell carcinomas, is originated from the nasopharynx. NPC possesses a high incidence in Southern China and Southeast Asia. To identify and understand the genetic events that drive these cancers is critical for the development of effective strategies for diagnosis, prognosis and therapy. Here, we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 70 pairs of NPC tissues. Overall, NPC has a relative low mutation rates. Our whole-exome squencing identified a total of 3420 somatic gene mutations, in which 59 genes had a mutation rate more than 4% and genes including CYLD, TP53, TTN etc were ranked as the most frequently mutated genes. Furthermore, two analysis protocols were applied to dissect the signaling pathways enriched by these 3420 mutation genes. The MetaCore algorithm found that these mutations were enriched in 329 pathways including platelet activating factor signaling, and regulation of GSK3 beta pathways etc. In addition, the KEGG prediction strategy revealed 28 signaling pathways that were tightly associated with samll cell lung cancer,chronic myeloid leukemia and non small cell lung cancer. Although numerous further inverstigations are urgent to decipher the clinical significance, mechanisms and dysfunction associated with these gene mutations, our whole-exom sequencing data establishes a solid and comprehensive mutation landscape in patients with NPC. These data will greatly beneficial to our deep understanding of the pathogenesis and tumorigenesis of NPC, and then accelerate to discover novel prognostic biomarker and promising therapeutic target.