Polarization of cells into a protrusive front and a retracting cell body is the hallmark of mesenchymal-like cell migration. Many mRNAs are localized to protrusions, but it is unclear to what degree mRNA localization contributes toward protrusion formation. We performed global quantitative analysis of the distributions of mRNAs, proteins, and translation rates between protrusions and the cell body by RNA sequencing (RNA-seq) and quantitative proteomics. Our results reveal local translation as a key determinant of protein localization to protrusions. Accordingly, inhibition of local translation destabilizes protrusions and inhibits mesenchymal-like morphology. Interestingly, many mRNAs localized to protrusions are translationally repressed. Specific cis-regulatory elements within mRNA UTRs define whether mRNAs are locally translated or repressed. Finally, RNAi screening of RNA-binding proteins (RBPs) enriched in protrusions revealed trans-regulators of localized translation that are functionally important for protrusions. We propose that by deciphering the localized mRNA UTR code, these proteins regulate protrusion stability and mesenchymal-like morphology. •Local translation is a key regulator of protein localization to cell protrusions•Localization of mRNAs alone, however, does not determine local protein expression•Specific UTR elements and RBPs are associated with local translation in protrusions•Inhibition of local translation destabilizes protrusions Establishment of front-back cell polarity is the first step in any form of active cell migration. Mardakheh et al. show that in mesenchymal-like cells, front-back asymmetry at the proteome level is maintained by differential local synthesis of cellular proteins.