Increasing evidence suggests that alterations in ribosome biogenesis (RiBi) confer competitive advantages to cancer cells. This has led to the discovery of regulatory layers mediated by signaling proteins, oncoproteins, and tumor suppressors whose deregulation leads to increased RiBi rates in cancer cells. In addition to boosting protein synthesis, these alterations probably contribute to shape the protumorigenic proteome of cancer cells. Mutations negatively affecting RiBi are also unexpectedly found in some spontaneous and ribosomopathy-associated tumors. The advantages provided by these genetic lesions to cancer cells remain unsettled as yet. Efforts are being made nowadays to exploit RiBi-associated vulnerabilities and tumor suppressor pathways to design new therapeutic avenues. In this review, we will summarize the main developments and pending challenges in this research area.