Molecular testing for head and neck squamous mucosal lesions and salivary gland tumors is becoming part of routine practice. Viral oncogenesis is implicated in both head and neck squamous cell carcinoma and nasopharyngeal carcinoma. Human papillomavirus (HPV) is detected in a majority of oropharyngeal squamous cell carcinomas and is associated with improved response to treatment. Detection of Epstein Barr Virus (EBV) in nasopharyngeal carcinoma is diagnostically useful. For salivary gland tumors, characteristic translocations with resultant fusion oncogenes have been identified. These genetic rearrangements can be detected by fluorescence in situ hybridization (FISH) testing and have diagnostic utility. These oncogenes also provide hope as therapeutic targets. ERBB2 (HER2) is one therapeutic target that has a role in salivary duct carcinoma. A subset of this tumor overexpresses ERBB2, and stabilization of disease has been reported with trastuzumab therapy.