RNA-binding proteins (RBPs) are important regulators of gene expression, but few have been studied for their role in malignancy. Using proteo-genomic techniques, we have identified the RBP CELF1 mRNA alternative splicing, translation and turnover targets in oral cancer cells. SILAC and Mass spectrometry analysis, identified 1322 proteins translationally controlled by CELF1 and many of these altered proteins were implicated in malignancy. Our genomic and proteomic analyses provided a comprehensive view of the CELF1 mRNA regulatory network in oral cancer and suggests that CELF1 is a viable target for therapeutic intervention.