Tumor Necrosis Factor (TNF) family of cytokines play important roles in various physiological and pathological processes, including cell proliferation, differentiation, apoptosis, modulation of immune response, and induction of inflammation. B-Cell Activating Factor (BAFF) is a TNF-related ligand that promotes B-Cell survival. It is expressed on dendritic cells, monocytes/macrophages, and T-Cells. BAFF is a positive regulator of B-Cell function, with effects on cell survival, activation, and differentiation. BAFF is found as homotrimer membrane-bound form in T-Cells and in a soluble form after cleavage by furin-type convertases that is released from the cell to stimulate B-Cell proliferation and differentiation. BAFF binds to three receptors: BCMA (B-Cell Maturation Antigen), TACI (Transmembrane Activator and Cyclophilin Ligand Interactor) and BAFFR (BAFF Receptor). Expression of BCMA and BAFFR is B-Cell specific, whereas TACI can be found on B-Cells and on subsets of activated T cells. Moreover, BAFF shares two receptors TACI and BCMA with another TNF-like ligand named APRIL (A Proliferation-Inducing Ligand), which is involved in tumor cell growth.BCMA is a 25kDa glycolipid anchored protein. The N-terminal part of proteins contains a conserved six-cysteine motif. The six-cysteine motif of BCMA is not the canonical motif of TNFRs (TNF Receptors) but corresponds to a variant motif present in the fourth repeat of the TNFRI molecule. BCMA can activate the transcription factor NF-κB (Nuclear Factor-κB) through TRAF5 (TNF Receptor-Associated Factor-5), TRAF6 (TNF Receptor-Associated Factor-6), TRAF3 (TNF Receptor-Associated Factor-3), NIK (NF-κB Inducing Kinase), and IKK (I-κB Kinase) dependent pathway. Engagement of BCMA also activates JNK (Jun N-terminal Kinases), p38 MAPK (Mitogen Activated Protein Kinase) and the transcription factor Elk1. The intracellular domain of TACI associates with TRAFs and activates NF-κB, NFAT (Nuclear Factor of Activated T-Cells) and JNK, thus presumably transducing signals for B-Cell proliferation and survival. BAFFR contains only four cysteine residues in its extracellular or ligand binding domain, making it the smallest CRD (Cysteine-Rich Domain) in the TNF receptor family. The binding of BAFF to BAFFR is primarily responsible for supporting transitional B-Cell maturation and enhancing the survival of mature B-Cells. Increased BAFF-mediated B-Cell survival has also been shown to enhance humoral immune responses. The identification of BCMA as a NF-κB-activating receptor for BAFF suggests molecular targets for drug development against certain immunodeficient or autoimmune diseases. Manipulation of the BAFF/BCMA-signaling system may provide novel approaches for modulation of B-Cell mediated immune responses and autoimmune diseases, such as Lupus and rheumatoid arthritis.