Significance MicroRNAs (miRNAs) can regulate the amounts of specific proteins by targeting their mRNA. miR-504, which targets the mRNA encoding the p53 tumor suppressor, resides within an intron of the fibroblast growth factor 13 ( FGF13 ) gene. We show that expression of the FGF13/miR-504 locus is repressed by p53, defining an additional p53-regulatory feedback loop. Moreover, we report that the FGF13 protein, whose expression is upregulated in a subset of tumors, is essential for survival of cells derived from such tumors. Remarkably, FGF13 restricts the production of ribosomal RNA and attenuates protein synthesis. By tuning down protein synthesis, FGF13 upregulation might enable oncogene-driven cancer cells to avoid excessive accumulation of potentially toxic aberrant proteins, conferring a survival advantage. This work defines a unique vulnerability of cancer cells.