The article reviews the role of Bruton tyrosine kinase (BTK) in B cell malignancies and the development of BTK inhibitors (BTKi) as a therapeutic strategy. BTK is a key component in the B cell receptor (BCR) signaling pathway, which is constitutively active in B cell neoplasms, leading to continuous BTK signaling and providing a survival and proliferation advantage to the neoplastic clone. Covalent BTKi, such as ibrutinib, acalabrutinib, and zanubrutinib, irreversibly block BTK by binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain. These drugs have shown significant efficacy in treating B cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL), and diffuse large B cell lymphoma (DLBCL). However, a significant fraction of patients experience disease relapse due to resistance mechanisms, including Cys-481 mutations of BTK. Non-covalent BTKi, such as pirtobrutinib, have been developed and shown effectiveness in patients with both Cys-481-mutated and unmutated BTK. Additionally, targeting BTK with proteolysis-targeting chimeras (PROTACs) represents a promising strategy to overcome resistance to BTKi in B cell neoplasms. The article highlights the progress made in the treatment of B cell neoplasms and the ongoing research to develop new therapeutic approaches.The article reviews the role of Bruton tyrosine kinase (BTK) in B cell malignancies and the development of BTK inhibitors (BTKi) as a therapeutic strategy. BTK is a key component in the B cell receptor (BCR) signaling pathway, which is constitutively active in B cell neoplasms, leading to continuous BTK signaling and providing a survival and proliferation advantage to the neoplastic clone. Covalent BTKi, such as ibrutinib, acalabrutinib, and zanubrutinib, irreversibly block BTK by binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain. These drugs have shown significant efficacy in treating B cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL), and diffuse large B cell lymphoma (DLBCL). However, a significant fraction of patients experience disease relapse due to resistance mechanisms, including Cys-481 mutations of BTK. Non-covalent BTKi, such as pirtobrutinib, have been developed and shown effectiveness in patients with both Cys-481-mutated and unmutated BTK. Additionally, targeting BTK with proteolysis-targeting chimeras (PROTACs) represents a promising strategy to overcome resistance to BTKi in B cell neoplasms. The article highlights the progress made in the treatment of B cell neoplasms and the ongoing research to develop new therapeutic approaches.