The article reviews the role of Bruton tyrosine kinase (BTK) in B cell malignancies, focusing on the mechanism of action of BTK inhibitors (BTKi) and resistance mechanisms. BTK is a key signaling molecule in B cell development and survival, and its activation contributes to the pathogenesis of B cell neoplasms. BTKi, such as ibrutinib, acalabrutinib, and zanubrutinib, are covalent inhibitors that irreversibly block BTK by binding to Cys-481 in the ATP-binding domain. These drugs have shown significant efficacy in treating B cell malignancies like chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL), and diffuse large B cell lymphoma (DLBCL). However, resistance to BTKi is a major challenge, with mechanisms including Cys-481 mutations in BTK, PLCG2 mutations, and other genetic alterations. Non-covalent BTKi, such as pirtobrutinib, have shown effectiveness in patients with Cys-481 mutations. Additionally, proteolysis-targeting chimeras (PROTACs) are emerging as a promising strategy to overcome BTKi resistance by degrading BTK. The article also discusses the development of BTK degraders, such as NX-2127, which show potential in overcoming resistance in patients with multiple lines of therapy. Overall, the review highlights the importance of understanding resistance mechanisms to improve treatment outcomes in B cell malignancies.The article reviews the role of Bruton tyrosine kinase (BTK) in B cell malignancies, focusing on the mechanism of action of BTK inhibitors (BTKi) and resistance mechanisms. BTK is a key signaling molecule in B cell development and survival, and its activation contributes to the pathogenesis of B cell neoplasms. BTKi, such as ibrutinib, acalabrutinib, and zanubrutinib, are covalent inhibitors that irreversibly block BTK by binding to Cys-481 in the ATP-binding domain. These drugs have shown significant efficacy in treating B cell malignancies like chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL), and diffuse large B cell lymphoma (DLBCL). However, resistance to BTKi is a major challenge, with mechanisms including Cys-481 mutations in BTK, PLCG2 mutations, and other genetic alterations. Non-covalent BTKi, such as pirtobrutinib, have shown effectiveness in patients with Cys-481 mutations. Additionally, proteolysis-targeting chimeras (PROTACs) are emerging as a promising strategy to overcome BTKi resistance by degrading BTK. The article also discusses the development of BTK degraders, such as NX-2127, which show potential in overcoming resistance in patients with multiple lines of therapy. Overall, the review highlights the importance of understanding resistance mechanisms to improve treatment outcomes in B cell malignancies.