Salivary gland carcinomas are a heterogeneous group of tumors with different biologic behavior. Given the lack of large randomized studies, there is no standard treatment for advanced and/or metastatic salivary gland tumors, and systemic therapy is empirically based. Tumor-specific recurrent chromosomal translocations and fusion oncogenes in aggressive head and neck malignancies have diagnostic, therapeutic, and prognostic implications. Pathognomonic fusion transcripts have been identified in subsets of mucoepidermoid carcinoma and adenoid cystic carcinoma. These translocations target 1) transcription factors involved in growth factor signaling and cell cycle regulation, 2) transcriptional co-activators, and 3) tyrosine kinase receptors. Prioritizing studies with a translational component to advance the molecular understanding of these cancers and molecular-targeted therapy clinical trials is critical.