Alterations in ErbB2 or fibroblast growth factor receptor-4 (FGFR-4) expression and activity occur in a significant fraction of breast cancers. Because signaling molecules and pathways cooperate to drive cancer progression, simultaneous targeting of multiple pathways is an appealing therapeutic strategy. With this in mind, we examined breast tumor cells for their sensitivity to the ErbB2 and FGFR inhibitors, PKI166 and PD173074, respectively. Simultaneous blocking of ErbB2 and FGFR-4 in MDA-MB-453 tumor cells had a stronger anti-proliferative effect than treatment with individual inhibitors. Examination of cell cycle regulators revealed a novel translation-mediated mechanism whereby ErbB2 and FGFR-4 cooperate to regulate cyclin D1 levels. Our results showed that FGFR-4 and ErbB2 via the MAPK and the phosphatidylinositol 3-kinase/protein kinase B pathways, respectively, both contribute to the maintenance of constitutive activity of the mammalian target of rapamycin translational pathway. Dual inhibition of these receptors strongly blocked S6 kinase 1 (S6K1) activity and cyclin D1 translation, as attested by a decrease in cyclin D1 mRNA association with polysomes. Ectopic expression of active protein kinase B or active S6K1 abrogated the dual inhibitor-mediated down-regulation of cyclin D1 expression, demonstrating the importance of these FGFR-4/ErbB2 signaling targets in regulating cyclin D1 translation. S6K1 has the central role in this process, since small interfering RNA-targeted S6K1 depletion led to a decrease in cellular S6K1 activity and, as a consequence, repression of cyclin D1 expression. Thus, we propose a novel mechanism for controlling cyclin D1 expression downstream of combined activity of ErbB2 and FGFR-4 that involves S6K1-mediated translation.