Abstract: Bruton tyrosine kinase (BTK) is a nonreceptor tyrosine kinase playing a key role in B cell antigen receptor (BCR) signal transduction. Activation of BCR signaling pathway is involved in the pathogenesis of multiple B cell malignancies, including chronic lymphocytic leukemia (CLL). In recent years, the application of covalent BTK inhibitors (BTKi) such as ibrutinib, has revolutionized the treatment of CLL. BTKi target tumor cells as well as microenvironment to induce apoptosis. Novel non-covalent BTKi has shown promising efficacy and safety profile, which may overcome drug resistance and intolerability of classic covalent BTKi. In this review, we discussed the mechanisms and clinical studies of both covalent and non-covalent BTKi in CLL so as to provide reference for basic research and clinical application of BTKi.