The article by Shibue and Weinberg explores the relationship between epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) in the context of drug resistance and clinical implications. The authors highlight that intratumoural heterogeneity, driven by the EMT program and the presence of CSCs, is a major factor in the development of acquired drug resistance in cancer. They discuss how the EMT program, which induces phenotypic changes in carcinoma cells without altering their genetic makeup, is linked to the CSC state, enabling tumor cells to self-renew and differentiate into less tumorogenic cells. The review also examines the role of the tumor microenvironment, including carcinoma-associated fibroblasts (CAFs) and inflammatory cells, in regulating EMT. Additionally, it explores the connection between EMT and CSCs in metastasis formation, suggesting that EMT-activated cells have enhanced metastasis-seeding abilities. The authors emphasize the need to understand the molecular mechanisms behind the EMT-CSC link to develop more effective therapeutic strategies. They conclude by discussing the challenges and opportunities in targeting the EMT program and CSCs to improve cancer treatment outcomes.The article by Shibue and Weinberg explores the relationship between epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) in the context of drug resistance and clinical implications. The authors highlight that intratumoural heterogeneity, driven by the EMT program and the presence of CSCs, is a major factor in the development of acquired drug resistance in cancer. They discuss how the EMT program, which induces phenotypic changes in carcinoma cells without altering their genetic makeup, is linked to the CSC state, enabling tumor cells to self-renew and differentiate into less tumorogenic cells. The review also examines the role of the tumor microenvironment, including carcinoma-associated fibroblasts (CAFs) and inflammatory cells, in regulating EMT. Additionally, it explores the connection between EMT and CSCs in metastasis formation, suggesting that EMT-activated cells have enhanced metastasis-seeding abilities. The authors emphasize the need to understand the molecular mechanisms behind the EMT-CSC link to develop more effective therapeutic strategies. They conclude by discussing the challenges and opportunities in targeting the EMT program and CSCs to improve cancer treatment outcomes.