Multiple myeloma (MM) is a late-stage B cell malignancy that has received much attention recently because of its therapeutic susceptibility to proteasome inhibitors. Two papers in this issue of Cancer Cell show that primary MM samples and MM cell lines frequently have mutations in genes encoding regulators and effectors of NF-kappaB signaling, and that these mutations lead to chronic NF-kappaB target gene expression, which is required for the viability of these MM tumor cells. These results reveal the molecular basis for constitutive NF-kappaB activity in many MMs and further validate the NF-kappaB signaling pathway as an appropriate target for MM therapy.