Ribosomopathies are a group of rare diseases caused by impaired ribosome biogenesis and/or function. While these disorders are all associated with ribosome dysfunction caused by mutations in ribosomal proteins or ribosome assembly factors, affected individuals exhibit diverse phenotypes, including bone marrow failure, craniofacial malformations, and increased cancer risk. The most common ribosomopathies include the inherited bone marrow failure syndromes (IBMFSs), Diamond–Blackfan anemia (DBA) syndrome, Shwachman–Diamond syndrome (SDS), dyskeratosis congenita (DC), cartilage–hair hypoplasia (CHH), and the neurocristopathy Treacher Collins syndrome (TCS). The clinical phenotype in affected patients likely reflects the complex interplay between ribosome deficiency, reduced protein synthesis, and the failure to efficiently translate key transcripts. While compensatory adaptive cellular responses, such as ribosome rescue and convergent somatic evolution, may restore ribosome homeostasis and cellular fitness, these mechanisms are overwhelmed, this results in p53 activation, cell cycle arrest, and cell senescence. Although a loss of p53 function may restore cell fitness, it also sets up the opportunity for p53-mutated cancer evolution.