Elucidation of oncogenic signaling in mantle cell lymphoma highlights opportunities for rational therapeutic combinations. B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) activates the CARD11-BCL10-MALT1 (CBM) complex, which induces NF-κB nuclear translocation and transcriptional activation of target genes, including antiapoptotic BCL2A1. Cell-extrinsic input from lymphoid-like cells in the microenvironment also signals through NF-κB to upregulate antiapoptotic genes, like BCL2L1 (Bcl-xL). These and other biological programs converge to promote targeted therapy resistance in mantle cell lymphoma but are subject to targeted inhibition by ibrutinib (BTK), venetoclax (BCL2 family peptides), and obinutuzumab (CD20, indirectly downregulating Bcl-xL). Here, Decombis et al have identified gain-of-function mutations in CARD11 that confer autonomous activation of the CBM complex, thereby circumventing pharmacologic inhibition of BTK with ibrutinib and potentially mediating resistance to combined BTK-BCL2-CD20 triplet therapy, as in the OAsIs trial. This illuminated the potential for therapeutic targeting of MALT1 to suppress the CBM–NF-κB–BCL2A1 resistance axis in mantle cell lymphoma as part of future rational combination regimens. BAFF, B-cell activating factor; IGF, insulin-like growth factor; IL, interleukin; PKC, protein kinase C; PLC, phospholipase C; SYK, spleen associated tyrosine kinase. Professional illustration by Somersault18:24.