B-cell activating factor (BAFF), as a member of the tumor necrosis factor (TNF) ligand family, plays important roles in B-cell homeostasis, tolerance, and malignancy. BAFF binds to three receptors of TNF, TACI, BCMA and BAFF-receptor (BAFF-R). In particular, the BAFF/BAFF-R pathway is crucial to the survival and growth of mature normal and malignant B-cells. BAFF is displayed on the cell surface or is released in a soluble form after cleavage from the plasma membrane. BAFF-R as the main BAFF receptor is expressed mainly on B-cells. Aberrant BAFF expression was found in malignant B-cells from B-cell non-Hodgkin lymphoma (B-NHL) patients, which protects these cells from spontaneous or drug-induced apoptosis and stimulated NF-κB activation via autocrine and/or paracrine pathways. However, the mechanisms involved in the gene expression and regulation of BAFF or BAFF-R has not been elucidated. More importantly, the design of reagents able to counteract BAFF/BAFF-R pathways may be of therapeutic value for B-NHL. Results of ongoing clinical trials with BAFF or BAFF-R antagonists are eagerly awaited.