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The highly conserved Hedgehog (HH) signaling pathway performs multiple roles in both development and tissue homeostasis, and its aberrant regulation is known to drive the pathogenesis of numerous human malignancies. However, the role of HH signaling in mediating disease progression and drug resistance remains unclear. This is especially true for myeloid malignancies. The HH pathway, and in particular the protein Smoothened (SMO), has been shown to be essential for regulating stem cell fate in chronic myeloid leukemia (CML). Evidence suggests that HH pathway activity is critical for maintaining the drug-resistant properties and survival of CML leukemic stem cells (LSCs), and that dual inhibition of BCR-ABL1 and SMO may comprise an effective therapeutic strategy for the eradication of these cells in patients. This review will explore the evolutionary origins of HH signaling, highlighting its roles in development and disease, which are mediated by canonical and non-canonical HH signaling. Development of small molecule inhibitors of HH signaling and clinical trials using these inhibitors as therapeutic agents in cancer and their potential resistance mechanisms, are also discussed, with a focus on CML.<\/jats:p>","DOI":"10.3390\/pharmaceutics15030958","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T03:50:45Z","timestamp":1678938645000},"page":"958","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia"],"prefix":"10.3390","volume":"15","author":[{"given":"Andrew","family":"Wu","sequence":"first","affiliation":[{"name":"Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada"},{"name":"Interdisciplinary Oncology, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly A.","family":"Turner","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada"},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Woolfson","sequence":"additional","affiliation":[{"name":"Replay Holdings Inc., 5555 Oberlin Drive, San Diego, CA 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8974-7340","authenticated-orcid":false,"given":"Xiaoyan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada"},{"name":"Interdisciplinary Oncology, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/287795a0","article-title":"Mutations Affecting Segment Number and Polarity in Drosophila","volume":"287","author":"Wieschaus","year":"1980","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1242\/dev.083691","article-title":"Roles for Hedgehog Signaling in Adult Organ Homeostasis and Repair","volume":"141","author":"Petrova","year":"2014","journal-title":"Development"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1006\/dbio.1995.0010","article-title":"HedgehogandBmpGenes Are Coexpressed at Many Diverse Sites of Cell\u2013Cell Interaction in the Mouse Embryo","volume":"172","author":"Bitgood","year":"1995","journal-title":"Dev. 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