Ribosomes are heterogeneous in terms of their constituent proteins, structural RNAs and ribosomal RNA (rRNA) modifications, resulting in diverse potential translatomes. rRNA modifications, guided by small nucleolar RNAs (snoRNAs), enable fine-tuning of ribosome function and translation profiles. Recent studies have begun linking dysregulation of snoRNAs, via rRNA modifications, to tumourigenesis. Deciphering the specific contributions of individual rRNA modifications to cancer hallmarks and identifying snoRNAs with oncogenic potential could lead to novel therapeutic strategies. These strategies might target snoRNAs or exploit the dependence of cancer cells on specific rRNA modification sites, potentially disrupting aberrant ribosomal translation programs and hindering tumour growth. This review discusses current evidence and challenges in linking changes in snoRNA expression to rRNA modification and cancer biology.This article is part of the discussion meeting issue 'Ribosome diversity and its impact on protein synthesis, development and disease'.