Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib (PCI-32765) is a novel targeted-therapeutic agent modulating BCR, which serves as a covalent irreversible inhibitor of BTK. Ibrutinib significantly alters the composition of the tumor microenvironment in CLL, affecting soluble as well as cellular molecular elements without myelosupression. Ibrutinib is clinically developed as an orally administered anti-cancer agent with lead indications in relapse/refractory and in treatment-naive patients with B-cell malignancies as a single agent. The clinical activities of Ibrutinib as a drug were shown in the B-cell malignancies, especially in patients with CLL, mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia (WM). Ibrutinib has generated the most extensive results so far in patients with CLL, predominately refractory or relapsed CLL where durable disease control as well as improved progression-free survival (PFS) and overall survival (OS) has been observed. The aim of this review is to outline the pharmacophysiological basis of Ibrutinib treatment as well as the current clinical experience based on the trials. The treatment algorithms of B-lymphoproliferative diseases will continue to be revised to a more personalized approach to treat with improved efficacy devoid of unnecessary toxicity.