Gene testing is performed to identify 1) viral or bacterial genes, 2) somatic mutations, 3) germline mutations and 4) polymorphisms. Purposes of gene testing for malignant tumors is to diagnose disease or to predict prognosis, treatment effects, or unwanted adverse effects. HPV status is an indispensable factor for determining the optimal therapeutic strategy for patients with oropharyngeal cancer (OPC). The identification of EBV and HPV in metastatic lymph nodes is now mandatory to determine the primary site. CRT1-MAML2 fusion gene is strongly associated with mucoepidermoid carcinoma with a favorable prognosis. Tyrosine kinase of RET is constantly activated in RET/PTC somatic rearrangements, which leads to the development of papillary thyroid carcinoma. More than 90% of synovial sarcoma has a chromosomal translocation of t(X;18)(p11.2;q11.2), resulting in the fusion gene SYT-SSX. The anti-EGFR antibody, cetuximab, has little or no effect on tumors harboring KRAS mutation or certain genomic variants of EGFR, although these mutations are rare in head and neck cancer. A new risk-stratification strategy has been developed based on the type of RET gene mutation to inform the age at which prophylactic thyroidectomy should be performed in MEN2. Bilateral retinoblastoma (RB) and 15% of unilateral RB are expected to exhibit a germline RB1 mutation. Survivors of hereditary retinoblastoma have a higher risk of developing other cancers later in life. Multiple head and neck paragangliomas are common in patients with SDHD mutations, while malignant head and neck paraganglioma is mostly seen in patients with SDHB mutations. Heterozygous aldehyde dehydrogenase 2 contributes to a higher chance of esophageal cancer and OPC.