Abstract Disruption of ribosome biogenesis leads to the activation of the RP-MDM2-p53 pathway along with other yet to be identified pathways. Ribosome biogenesis is inherently tied to protein synthesis, a process relied upon in cancer to sustain its increased proliferative properties. The ability to activate a tumor suppressor and simultaneously target a process heavily dependent upon for cancer growth is a promising therapeutic angle that deserves exploration. In the present study, we knocked down expression of all large subunit ribosomal proteins to examine their effect on melanoma growth. We found that targeting many ribosomal proteins lead to decreased cancer cell viability. siRNA mediated knocking down of RPL13, a representative ribosomal protein of this group, resulted in increased p53 expression and cell cycle arrest dependent on the RP-MDM2-p53 pathway. Furthermore, inhibition of protein synthesis in culture and decreased tumor growth by 50-90% in animals was observed upon knockdown of RPL13. We conclude that the cell cycle arrest is due in large part to the increased p53 expression caused by the binding of RPL5 and RPL11 to MDM2, however the inhibition of melanoma growth cannot be explained solely by an increase in the tumor suppressor. The accompaniment of decreased protein synthesis provides an additional mechanism contributing to decreased growth. Thus, targeting ribosomal proteins in cancer may serve as an underappreciated therapeutic treatment. Citation Format: Gregory R. Kardos, Gavin P. Robertson. Targeting ribosomal proteins for therapeutic inhibition of melanoma growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4395. doi:10.1158/1538-7445.AM2013-4395