BTK inhibitors (BTKi) are key treatments for B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenstrom macroglobulinemia. First-generation BTKi, such as ibrutinib, showed significant efficacy but had cardiovascular side effects like atrial fibrillation and hypertension. Second-generation BTKi, including acalabrutinib and zanubrutinib, offer improved selectivity and reduced cardiovascular complications. These drugs are agnostic to the C481S mutation, which confers resistance to first-generation BTKi. However, they can lead to resistance mutations outside the C481 site. Newer BTK degraders are being developed to target both C481 and non-C481 mutations. Reversible, noncovalent BTKi like pirtobrutinib are effective against C481S mutations but may have resistance to other mutations. BTK degraders show promise in targeting various mutations. The emergence of BTK mutations has led to the development of new BTK-targeting therapies. Acalabrutinib and zanubrutinib have shown better safety profiles than ibrutinib in head-to-head trials. However, variant BTK mutations may be more common in patients treated with highly specific BTKi. Combining BTKi with other agents, such as BCL2 inhibitors like venetoclax, has shown potential for improved outcomes and reduced resistance. Studies have evaluated combination therapies with venetoclax and obinutuzumab, showing durable responses and improved PFS. The role of BTKi in first-line therapy and the need for individualized treatment based on BTK mutations are important considerations. Future research should focus on developing BTK-targeting therapies that account for the mutational spectrum of patients.BTK inhibitors (BTKi) are key treatments for B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenstrom macroglobulinemia. First-generation BTKi, such as ibrutinib, showed significant efficacy but had cardiovascular side effects like atrial fibrillation and hypertension. Second-generation BTKi, including acalabrutinib and zanubrutinib, offer improved selectivity and reduced cardiovascular complications. These drugs are agnostic to the C481S mutation, which confers resistance to first-generation BTKi. However, they can lead to resistance mutations outside the C481 site. Newer BTK degraders are being developed to target both C481 and non-C481 mutations. Reversible, noncovalent BTKi like pirtobrutinib are effective against C481S mutations but may have resistance to other mutations. BTK degraders show promise in targeting various mutations. The emergence of BTK mutations has led to the development of new BTK-targeting therapies. Acalabrutinib and zanubrutinib have shown better safety profiles than ibrutinib in head-to-head trials. However, variant BTK mutations may be more common in patients treated with highly specific BTKi. Combining BTKi with other agents, such as BCL2 inhibitors like venetoclax, has shown potential for improved outcomes and reduced resistance. Studies have evaluated combination therapies with venetoclax and obinutuzumab, showing durable responses and improved PFS. The role of BTKi in first-line therapy and the need for individualized treatment based on BTK mutations are important considerations. Future research should focus on developing BTK-targeting therapies that account for the mutational spectrum of patients.