Although salivary gland cancers comprise only ∼3-6% of head and neck cancers, treatment options for patients with advanced-stage disease are limited. Because of their rarity, salivary gland malignancies are understudied compared to other exocrine tissue cancers. The comparative lack of progress in this cancer field is particularly evident when it comes to our incomplete understanding of the key molecular signals that are causal for the development and/or progression of salivary gland cancers. Using a novel conditional transgenic mouse (K5:RANKL), we demonstrate that Receptor Activator of NFkB Ligand (RANKL) targeted to cytokeratin 5-positive basal epithelial cells of the salivary gland causes aggressive tumorigenesis within a short period of RANKL exposure. Genome-wide transcriptomic analysis reveals that RANKL markedly increases the expression levels of numerous gene families involved in cellular proliferation, migration, and intra- and extra-tumoral communication. Importantly, cross-species comparison of the K5:RANKL transcriptomic dataset with The Cancer Genome Atlas cancer signatures reveals the strongest molecular similarity with cancer subtypes of the human head and neck squamous cell carcinoma. These studies not only provide a much needed transcriptomic resource to mine for novel molecular targets for therapy and/or diagnosis but validates the K5:RANKL transgenic as a preclinical model to further investigate the in vivo oncogenic role of RANKL signaling in salivary gland tumorigenesis.