Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease whose pathogenesis is multifactorial lying on genetic, environmental factors and on abnormalities of both the innate and the adaptive immune system. The induction, maintenance and progression of the disease are a multi-step process that may take long time eventually leading to tissue injury. Several genes have been associated to SLE susceptibility; each of them displaying a small effect suggesting the need of an association. However, the gene–gene and gene–environment interactions are still matter of research. Environmental factors, both external such as physical and infectious agents and internal such as gender and hormonal profile, may influence the disease manifestation. SLE is characterized by a complex array of immune abnormalities affecting both the innate and the adaptive immunity. All these processes play a role in the defective clearance of chromatin material that is overexposed to the afferent limb of the immune system leading to an autoimmune response facilitated by defective regulatory mechanisms. The production of a wide panel of autoantibodies represents the ultimate events responsible for tissue aggression. Finally, tissue damage is influenced by the presence of local factors responsible for the final aggressivity of the lesions and of the clinical manifestations.