B-cell receptor (BCR) provides essential growth and survival signals to B-cell lymphomas. Inhibitors of BCR signaling have become an area of substantial clinical interest. We studied the role of BCR signaling in stroma-mediated cell survival and drug resistance in mantle cell lymphoma (MCL). We demonstrated that adhesion of MCL cells to lymph node stroma enhanced activation of BCR signaling: PI3Kδ, BTK and ERK pathways. Inhibition of BTK by PCI 32765 or PI3Kδ by CAL101 significantly blocked intrinsic and stroma-conferred BCR signaling, lymphoma-stroma interaction and triggered lymphoma cell apoptosis. Combined treatment of BTK and PI3Kδ inhibitors synergistically disrupt BCR-signaling, overcome microenvironment-mediated drug resistance, and suppress cyclin D1 expression and lymphoma cell growth in MCL cell lines and primary samples. Collectively, these data support that BCR activation controls intrinsic survival as well regulates stroma-mediated extrinsic lymphoma cell survival. Combined targeting of BCR pathway intermediates is a promising therapeutic strategy to MCL therapy.