B-cell non-Hodgkin lymphomas and leukaemias comprise ~3.5% of all cancer diagnoses in the United States and consist of a heterogeneous group of malignancies. Historically, the backbone of treatment has been cytotoxic chemotherapy, but in recent decades, targeted therapies have been incorporated into earlier line settings. The B-cell receptor (BCR) signalling pathway is a key driver of B-cell malignancies (Figure 1) and agents disrupting this pathway have changed the landscape of management in both the front-line and relapsed/refractory (R/R) settings. A key target is the Bruton tyrosine kinase (BTK), a component of early BCR signalling pathway. In normal B cells, BTK activation, reflected by its phosphorylation, triggers downstream events and ultimately, the activation of nuclear factor kappa B (NFκB) pathways enabling increased B-cell survival, proliferation, differentiation into plasma cells and subsequent antibody production 1,2 (Figure 1). In this review, we will discuss the use of BTK inhibitors (BTKi) in B-cell malignancies and cover the mechanisms of resistance. These understandings not only help improve care and survival of patients treated with BTKi, but also help direct BCR-targeted therapeutic strategies for future clinical trial design.The first in class BTKi is ibrutinib, an orally available small molecular inhibitor of the kinase. At the molecular level, the drug binds covalently to the cysteine 481 at the ATP binding site of BTK (Figure 2) to inhibit its activity and downstream signalling cascade. 3,4 At the cellular level, the consequence of BCR inhibition is primarily cell proliferation deceleration rather than direct cell killing. 5,6 Aside from cell proliferation, ibrutinib has demonstrated inhibitory effects