Ribosomes are a complex ensemble of ribosomal RNA (rRNA) and ribosomal proteins that function as mRNA translation machines. Ribosome biogenesis is a multi-step process that begins in the nucleolus and concludes in the cytoplasm. The process is tightly controlled by multiple checkpoint and surveillance pathways. Perturbations in these checkpoints and pathways can lead to hyper-activation of ribosome biogenesis. Emerging evidence suggests that cancer cells harbor a specialized class of ribosomes (onco-ribosomes) that facilitates the oncogenic translation program, modulates cellular functions, and promotes metabolic rewiring. Mutations in ribosomal proteins, rRNA processing, and ribosome assembly factors result in ribosomopathies that are associated with an increased risk of developing malignancies. Recent studies have linked mutations in ribosomal proteins and aberrant ribosomes with poor prognosis, highlighting ribosome-targeted therapy as a promising approach for treating cancer patients. Here we summarize various aspects of dysregulation of ribosome biogenesis and the impact of resultant onco-ribosomes on malignant tumor behavior, therapeutic resistance, and clinical outcome. Ribosome biogenesis is a promising therapeutic target, and understanding the important determinants of this process will allow for improved and perhaps selective therapeutic strategies to target ribosome biosynthesis.