Abnormal B-cell receptor (BCR) signaling is a key mechanism of disease progression in B-cell malignancy. Bruton's tyrosine kinase (BTK) has a pivotal role in BCR signaling. Ibrutinib (PCI-32765) is a novel agent which serves as a covalent irreversible inhibitor of BTK. It is characterized by high selectivity for BTK and high potency. Preliminary data from phase I and ongoing phase II trials have proven very promising so far. It suggests the substance has high efficacy in B-cell malignancies such as chronic lymphocytic leukemia (CLL); diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantel cell lymphoma (MCL), and multiple myeloma (MM) and is very well tolerable. Most notably, the substance does not cause myelosuppression. This chapter discusses structure, mechanism of action, and toxicities of ibrutinib and also presents important preclinical and clinical data. Phase III trials will have to determine the definite role of ibrutinib in clinical practice but the data available so far suggests it may be a powerful new weapon in the battle against B-cell malignancies.