A variety of immune mechanisms, both humoral and cellular, are involved in the onset and amplification of the inflammatory response in lupus nephritis (LN). Accumulating evidence substantiates the view that innate immunity pathways may also amplify inflammatory reactions within the kidneys. Toll-like receptors (TLRs) are essential modulators of the innate immune response thanks to their ability to rocognize conserved molecular patterns that are microbe specific and other danger signals. Their recognition of endogenous molecules released from injured cells may also contribute to renal inflammation. Studies conducted in vivo and in vitro provide experimental evidence for the functional role of TLRs in LN. Intriguingly, these data suggest that pharmacological TLR signal suppression could be a useful approach to the treatment of systemic lupus erythematosus.