Even though ibrutinib has been shown to be efficacious in difficult to treat B-cell malignancies, such as salvage therapy in mantle cell lymphoma and 17p- CLL, many of these patients will eventually relapse with ibrutinib-refractory disease.23, 24 Often these relapses are due to critical mutations in the BTK pathway that inhibit ibrutinib binding to the BTK protein (C481S)24 or activating mutations in (PLCγ2)24 that bypass the need for BTK's activity. The gene discussed is BTK; the disease is mantle cell lymphoma.