Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with diverse clinical features and involving multiple organs leading to highest mortality rate among rheumatic diseases. B cells are responsible and central to the pathogenesis of SLE progression by means of over-aggressive immune response. The complexity of clinical manifestations and unpredictability of the disease are the main hurdles in optimizing treatment for SLE. Recent developments in biological therapy generated hope in SLE patients. Belimumab (Benlysta®) is a complete human monoclonal antibody that is approved for SLE treatment. More or less, belimumab is the first approved biological drug from the Food and Drug Administration, United States (FDA), inhibiting B-cell activating factor/B-lymphocyte stimulator. The present review elucidates the cellular mechanism involved in SLE progression and therapeutic effective of belimumab including clinical trials and clinical outcomes.