Adherens junctions, which are intercellular adhesive complexes that are crucial for maintaining epithelial homeostasis, are downregulated in many cancers to promote tumour progression. However, the role of desmosomes — adhesion complexes that are related to adherens junctions — in carcinogenesis has remained elusive. Recent studies using mouse genetic approaches have uncovered a role for desmosomes in tumour suppression, demonstrating that desmosome downregulation occurs before that of adherens junctions to drive tumour development and early invasion, suggesting a two-step model of adhesion dysfunction in cancer progression.