The combination of the neoplastic accumulation of mature B lymphocytes with the presence of autoimmune phenomena is a characteristic finding in chronic B cell lymphoproliferative disorders, particularly chronic lymphocytic leukemia. Identification of mechanisms linking neoplasia to the autoimmune defects is important for a better understanding and improving the treatment of these conditions. Among such mechanisms, the B cell activator factor (BAFF) and a proliferation-inducing ligand (APRIL), two members of the tumor necrosis factor family, play an important role. BAFF and APRIL have both been associated with autoimmunity, with their underlying mechanism of action most likely being related to the rescue of autoreactive B cells. In addition, BAFF and APRIL are crucial in B cell development and homeostasis particularly via the activation of NF-kappaB pathway-mediated survival signals. These two proteins, therefore, constitute a paradigm of pathophysiological defects linking neoplasia and autoimmunity, thereby providing a better understanding of chronic B cell lymphoproliferative disorders.