In recent years, biomarkers have shown significant promise in helping decision-making in drug development. Systemic lupus erythematosus (SLE) is a complicated and highly heterogeneous disease that involves all organs. Only one drug, belimumab, has been approved by the US Food and Drug Administration to treat SLE during the last 50 years and there remains a high unmet medical need to develop new and effective therapies to benefit different patient populations in SLE. Due to the extreme heterogeneity of the disease and the complex and rigorous process to validate individual biomarkers, there is currently a very limited number of consensus biomarkers to aid the treatment decision-making in SLE. This review provides a snapshot of some biomarkers in the field that have the potential to make a big impact on drug development and/or treatment decisions by physicians. These include: type I interferon (IFN) gene signature as a pharmacodynamic marker and potential predictive marker for anti-type I IFN therapy; anti-double stranded DNA as a disease marker and potential predictive marker for flares; the complements and neutrophil signatures as disease marker of SLE; and TWEAK (a tumor necrosis factor family member produced by macrophages) and MCP-1 as potential markers to predict renal flares. Most of these markers need carefully planned and prospective studies with high statistical power to confirm their respective utilities. With the development and application of powerful new technologies, more successful biomarkers will emerge in SLE. This could improve the management of patients in the clinic and facilitate the development of novel and more effective therapeutics for this difficult-to-treat disease.