In view of the significant differences in genomic profile between HNSCC HPV(−) and HNSCC HPV(+), we reviewed the characterization of the genomic and expression profiles of TRAIL (TNFSF10) along with its receptors, FADD, BIRC2/3 and XIAP, in HNSCC tissues differing in HPV status. The gene discussed is TNFSF10; the disease is head and neck squamous cell carcinoma.