B lymphocyte stimulator (BLyS), also referred to as B cell activating factor of the TNF family, is a recently identified tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B cell development and homeostasis and it shares significant homology with another TNF superfamily member, a proliferation inducing ligand (APRIL). Currently, three receptors have been identified that transmit signals upon BLyS and APRIL binding and these include B cell maturation antigen, B cell activating factor receptor, and transmembrane activator and CAML interactor. The striking effects of BLyS on normal B cell maintenance and survival and the largely B lineage-restricted pattern of receptor expression, raises the possibility that these TNF family ligands and receptors may be involved not only in B cell autoimmunity, but also in the pathogenesis and maintenance of mature B lineage hematological malignancies. In this article, we will review the spectrum of human B lineage malignancies and discuss current evidence supporting a role for BLyS and APRIL in fueling the growth and survival of specific B cell malignancies.