The B-cell receptor (BCR) is essential for normal B-cell development and 
maturation. In an increasing number of B-cell malignancies, BCR signaling is 
implicated as a pivotal pathway in tumorigenesis. Mechanisms of BCR activation 
are quite diverse and range from chronic antigenic drive by microbial or viral 
antigens to autostimulation of B-cells by self-antigens to activating mutations 
in intracellular components of the BCR pathway. Hepatitis C virus infection can 
lead to the development of splenic marginal zone lymphoma, while Helicobacter 
pylori infection is associated with the development of mucosa-associated 
lymphoid tissue lymphomas. In some of these cases, successful treatment of the 
infection removes the inciting antigen and results in resolution of the 
lymphoma. Chronic lymphocytic leukemia has been recognized for decades as a 
malignancy of auto-reactive B-cells and its clinical course is in part 
determined by the differential response of the malignant cells to BCR 
activation. In a number of B-cell malignancies, activating mutations in signal 
transduction components of the BCR pathway have been identified; prominent 
examples are activated B-cell-like (ABC) diffuse large B-cell lymphomas (DLBCL) 
that carry mutations in CD79B and CARD11 and display chronic active BCR 
signaling resulting in constitutive activation of the NF-κB pathway. Despite 
considerable heterogeneity in biology and clinical course, many mature B-cell 
malignancies are highly sensitive to kinase inhibitors that disrupt BCR 
signaling. Thus, targeted therapy through inhibition of BCR signaling is 
emerging as a new treatment paradigm for many B-cell malignancies. Here, we 
review the role of the BCR in the pathogenesis of B-cell malignancies and 
summarize clinical results of the emerging class of kinase inhibitors that 
target this pathway.