Diffuse large B cell lymphoma (DLBCL) is a heterogeneous diagnostic category that is comprised of two prominent molecular subtypes, termed activated B cell-like (ABC) and germinal center B cell-like (GCB), which are now recognized as pathogenetically distinct diseases. Genetic screens using RNA interference and CRISPR-Cas9 have revealed different oncogenic signaling pathways in these DLBCL subtypes can be blocked by targeted therapeutic agents. We defined a “chronic active” form of B cell receptor (BCR) signaling that activates NF-kB in ABC DLBCLs. Such ABC DLBCLs are killed by knockdown of BCR signaling components, such as the kinase BTK or components of the BCR itself. Over one fifth of ABC DLBCLs have mutations affecting the CD79B or CD79A subunits of the BCR that augment BCR signaling. To attack chronic active BCR signaling therapeutically, we initiated clinical trials in relapsed/refractory DLBCL of ibrutinib, an irreversible and highly selective inhibitor of BTK. Ibrutinib monotherapy induced a high rate of complete and partial responses in ABC DLBCL, while GCB DLBCL tumors rarely responded. We have also defined other oncogenic signaling pathways in ABC DLBCL that cooperate with BCR signaling to sustain cell survival, including the MyD88 pathway, which is activated by oncogenic MYD88 mutations in ~40% of cases. DLBCL tumors with both MYD88 and CD79B mutations responded frequently to ibrutinib, revealing a functional crosstalk between the MYD88 and BCR pathways in ABC DLBCL these cases. The molecular and cellular mechanisms underlying this phenomenon have been revealed by CRISPR-Cas9 genetic screens and will be discussed. Finally, we predicted that another aggressive lymphoma type, termed primary central nervous system lymphoma (PCNSL), would respond well to ibrutinib since both CD79B and MYD88 are mutated in a higher percentage of cases. Encouraging data from a recently complete phase 1 study of ibrutinib plus chemotherapy in PCNSL will be presented.