The BCR signaling pathway as a therapeutic target for the BTK inhibitor ibrutinib. The BCR is composed of a membrane immunoglobulin bound to CD79A and CD79B. Binding of the BCR by antigens/autoantigens recruit tyrosine kinases, including spleen tyrosine kinase (SYK) and Src family kinases (SFK), to the immunoreceptor tyrosine-based activation motif domain of CD79A/CD79B. This initial step translates into activation of a number of signal transduction molecules, including rat sarcoma viral oncogene homolog (RAF)-murine leukemia viral oncogene (RAF)-ERK/MAPK, PI3K, and BTK. In the PI3K arm of the pathway, AKT and mTOR relay PI3K activation to downstream targets and cell cycle regulation. On activation by the BCR, PI3K also promotes a sustained calcium uptake. One of the targets regulated by calcium elevation is the transcription factor nuclear factor of activated T cells (NFAT), which activates prosurvival genes in B cells. The BTK arm of the pathway induces phosphorylation of phospholipase C-gamma (PLCγ), which in turn promotes the production of the signaling mediators diacylglycerol (DAG) and inositol trisphosphate (IP3) and thus activates protein kinase C (PKC)β. Subsequently, PKCβ leads to phosphorylation of caspase recruitment domain family, member 11 (CARD11), recruitment of mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) and B-cell CLL/lymphoma 10 protein (BCL10) into a multiprotein complex, and initiation of NF-κB signaling, that ultimately activates a transcriptional program of survival, proliferation, and migration. Ibrutinib is a selective tyrosine kinase inhibitor that covalently and irreversibly binds BTK and consequently blocks BCR signaling and survival, proliferation, and migration of CLL cells. Professional illustration by Marie Dauenheimer.