Several molecular pathways have been shown to play critical roles in the pathogenesis of odontogenic tumors. These neoplasms arise from the epithelial or mesenchymal cells of the dental apparatus in the jaw or oral mucosa. Next-generation genomic sequencing has identified gene mutations or single nucleotide polymorphisms associated with many of these tumors. In this review, we focus on two of the most common odontogenic tumor subtypes: ameloblastoma and keratocystic odontogenic tumors. We highlight gene expression and protein immunohistological findings and known genetic alterations in the hedgehog, BRAF/Ras/MAPK, epidermal growth factor receptor, Wnt, and Akt signaling pathways relevant to these tumors. These various pathways are explored to potentially target odontogenic tumor cells and prevent growth and recurrence of disease. Through an understanding of these signaling pathways and their crosstalk, molecular diagnostics may emerge as well as the ability to exploit identified molecular differences to develop novel molecular therapeutics for the treatment of odontogenic tumors.