Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that attacks various organ systems with a variety of clinical implications, ranging from mild skin and mucosal manifestations to severe central nervous system manifestations and death. Cases of SLE have been documented nearly two centuries ago when scholars used the terms ‘erythema centrifugum’ and ‘seborrhea congestiva’ to describe the discoid skin lesions and the butterfly or malar rash in SLE. Since then, knowledge about this disease has developed rapidly, especially knowledge related to the underlying pathogenesis of SLE. To date, it is known that immune system dysregulation, supported by genetic and environmental predisposition, can trigger the occurrence of SLE in a group of susceptible individuals. Various inflammatory mediators, cytokines and chemokines, as well as intra- and intercellular signaling pathways, are involved in the pathogenesis of SLE. In this review, we will discuss the molecular and cellular aspects of SLE pathogenesis, with a focus on how the immune system, genetics and the environment interact and trigger the various clinical manifestations of SLE.