Bruton tyrosine kinase (BTK) is a nonreceptor tyrosine kinase that plays a central role in the signal transduction of the B-cell antigen receptor and other cell surface receptors, both in normal and malignant B lymphocytes. B-cell antigen receptor signaling is activated in secondary lymphatic organs and drives the proliferation of malignant B cells, including chronic lymphocytic leukemia (CLL) cells. During the last 10 years, BTK inhibitors (BTKis) are increasingly replacing chemotherapy-based regimen, especially in patients with CLL and mantle cell lymphoma (MCL). Bruton tyrosine kinase inhibitors are particularly active in patients with CLL and MCL, but also received approval for Waldenström macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma, and chronic graft-versus-host disease. Current clinical practice is continuous long-term administration of BTKi, which can be complicated by adverse effects or the development of drug resistance. Alternatives to long-term use of BTKi are being developed, such as combination therapies, permitting for limited duration therapy. Second-generation BTKis are under development, which differ from ibrutinib, the first-in-class BTKi, in their specificity for BTK, and therefore may differentiate themselves from ibrutinib in terms of adverse effects or efficacy.