Developmental Hedgehog (Hh) signaling is found deregulated in a broad spectrum of human malignancies and, thus, is an attractive target for cancer therapy. Currently available Hh inhibitors have shown the rapid occurrence of drug resistance, due to altered signaling in collateral pathways. Emerging observations suggest that Hh signaling regulates protein translation in pathways that depend both on Cap- and IRES-mediated translation. In addition, translational regulators have been shown to modulate Hh function. In this opinion, we describe this novel Hh/translation crosstalk and argue that it plays a relevant role in Hh-mediated tumorigenesis and drug resistance. As such, we suggest that drugs targeting translation might be introduced in novel protocols aimed at treating malignancies driven by aberrant Hh signaling.