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Our review investigates various mechanisms of resistance to BCL2 inhibitors, including mutations in BCL2, alterations in the Bcl protein pathway, epigenetic modifications, genetic heterogeneity, Richter transformation, and alterations in oxidative phosphorylation. Additionally, the review will discuss potential avenues to overcome this resistance with novel agents such as bispecific antibodies, Bruton\u2019s tyrosine kinase (BTK) degraders, non-covalent BTK inhibitors, and chimeric antigen receptor T (CART).<\/jats:p>","DOI":"10.20517\/cdr.2023.97","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T07:38:46Z","timestamp":1701070726000},"page":"828-37","update-policy":"https:\/\/doi.org\/10.20517\/oae.crossmark.policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting BCL2 pathways in CLL: a story of resistance and ingenuity"],"prefix":"10.20517","volume":"6","author":[{"given":"Amanda","family":"Reyes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanya","family":"Siddiqi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"8410","published-online":{"date-parts":[[2023,11,27]]},"reference":[{"key":"B1","unstructured":"Chronic lymphocytic leukemia - Chronic lymphocytic leukemia (CLL). 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