BTK is critical for oncogenic signaling in multiple B-cell malignancies including mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and Waldenström’s macroglobulinemia (WM). Malignant B cell survival, proliferation, and interactions with the tumor microenvironment require BTK. In MCL, BTK is essential for retention of cancer cells in lymphoid tissues. Constitutively active pathways essential for CLL survival require BTK. Phosphorylated BTK triggers NF-kb signaling in WM leading to survival and proliferation and BTK mediated NF-kb signaling is known to play an important role in FL as well.