Renal disease is one of the most severe aspects of systemic lupus erythematosus (SLE), potentially leading to irreversible kidney failure. The standard of care for severe lupus nephritis involves the use of high-dose corticosteroids, cyclophosphamide and other immunosuppressive drugs. Although these drugs are effective in controlling disease activity in the majority of patients, up to 25% of patients treated with cyclophosphamide-based protocols develop renal insufficiency and end-stage renal disease, and treatment discontinuation is associated with the occurrence of flares. Furthermore, these therapies are associated with a high incidence of short- and long-term side effects. LJP-394 (abetimus sodium) is an investigational agent specifically designed to decrease anti-dsDNA antibody levels, and it is under development for the prevention of nephritic flares in patients with SLE since the early 1990s. The drug has been evaluated in 13 clinical trials that evaluated > 800 patients with SLE, over a 10-year time span. It is likely that LJP-394 might have a role in the prevention of renal flares in SLE patients, and if the initial data is confirmed in an ongoing trial, this drug could represent either a substitute for immunosuppressive drugs or could allow a reduction of their dose, thereby reducing the risks of short- and long-term side effects. This paper reviews the principal aspects of chemistry, pharmacokinetics, efficacy and safety of LJP-394, and analyses studies on animal models and clinical studies conducted in the last few years.