Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a recently identified proinflammatory cytokine of the TNF superfamily that functions through binding to Fn14 receptor in target cells. TWEAK has multiple biological activities. Studies show that TWEAK plays an important role in immune inflammatory diseases. Recent work has revealed that TWEAK may play an important role in the pathogenesis of kidney damage, including in systemic lupus erythematosus (SLE), where its concentration in urine was correlated with the level of activity of lupus nephritis (LN). The major focus of this review is to discuss the recent studies on TWEAK and its possible role in the pathogenesis of LN, and the therapeutic potential of modulating this pathway in LN. TWEAK plays a key role in the pathogenesis of LN through activation of multiple down-signaling pathway, inducing proinflammatory cytokines and chemokines, affecting cell proliferation/apoptosis and inducing renal IgG deposition. TWEAK blockade may be a novel therapeutic approach to reducing renal damage in SLE.