BTK inhibitors (BTKi) have become a cornerstone in the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenstrom macroglobulinemia. The first-generation BTKi, ibrutinib, demonstrated significant efficacy in clinical trials but was associated with cardiovascular side effects such as atrial fibrillation and hypertension. Second-generation BTKi, including acalabrutinib and zanubrutinib, showed improved selectivity and reduced cardiovascular complications, with favorable safety profiles in head-to-head trials. These drugs are agnostic to the C481S mutation, a common resistance mechanism, but can lead to resistance through other mutations. Reversible, noncovalent BTKi like pirtobrutinib offer a different approach, avoiding covalent binding to BTK, but may still face resistance through variant mutations. BTK protein degraders are currently in clinical development, targeting BTK regardless of mutations. The evolution of BTK-targeting therapies highlights the ongoing challenge of managing resistance and optimizing treatment strategies. As resistance mutations emerge, new therapeutic approaches, including combination therapies with BCL2 inhibitors and immunotherapies, are being explored to improve outcomes for patients with CLL. The future of BTKi therapy involves addressing resistance mechanisms, refining treatment sequencing, and integrating new therapeutic strategies to achieve durable remissions and long-term survival.BTK inhibitors (BTKi) have become a cornerstone in the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenstrom macroglobulinemia. The first-generation BTKi, ibrutinib, demonstrated significant efficacy in clinical trials but was associated with cardiovascular side effects such as atrial fibrillation and hypertension. Second-generation BTKi, including acalabrutinib and zanubrutinib, showed improved selectivity and reduced cardiovascular complications, with favorable safety profiles in head-to-head trials. These drugs are agnostic to the C481S mutation, a common resistance mechanism, but can lead to resistance through other mutations. Reversible, noncovalent BTKi like pirtobrutinib offer a different approach, avoiding covalent binding to BTK, but may still face resistance through variant mutations. BTK protein degraders are currently in clinical development, targeting BTK regardless of mutations. The evolution of BTK-targeting therapies highlights the ongoing challenge of managing resistance and optimizing treatment strategies. As resistance mutations emerge, new therapeutic approaches, including combination therapies with BCL2 inhibitors and immunotherapies, are being explored to improve outcomes for patients with CLL. The future of BTKi therapy involves addressing resistance mechanisms, refining treatment sequencing, and integrating new therapeutic strategies to achieve durable remissions and long-term survival.