Abstract: Systemic Lupus Erythematosus (SLE) or Lupus is a multifactorial autoimmune disease of multiorgan malfunctioning of extremely heterogeneous and unclear etiology that affects multi-ple organs and physiological systems. Some racial groups and women of childbearing age are more susceptible to SLE pathogenesis. Impressive progress has been made towards a better under-standing of different immune components contributing to SLE pathogenesis. Recent investigations have uncovered the detailed mechanisms of inflammatory responses and organ damage. Various environmental factors, pathogens, and toxicants, including ultraviolet light, drugs, viral pathogens, gut microbiome metabolites, and sex hormones trigger the onset of SLE pathogenesis in genetical-ly susceptible individuals and result in the disruption of immune homeostasis of cytokines, macro-phages, T cells, and B cells. Diagnosis and clinical investigations of SLE remain challenging due to its clinical heterogeneity and hitherto only a few approved antimalarials, glucocorticoids, im-munosuppressants, and some nonsteroidal anti-inflammatory drugs (NSAIDs) are available for treatment. However, the adverse effects of renal and neuropsychiatric lupus and late diagnosis make therapy challenging. Additionally, SLE is also linked to an increased risk of cardiovascular diseases due to inflammatory responses and the risk of infection from immunosuppressive treat-ment. Due to the diversity of symptoms and treatment-resistant diseases, SLE management re-mains a challenging issue. Nevertheless, the use of next-generation therapeutics with stem cell and gene therapy may bring better outcomes to SLE treatment in the future. This review highlights the autoimmune responses as well as potential therapeutic interventions for SLE particularly focusing on the recent therapeutic advancements and challenges.