Systemic lupus erythematosus (SLE) is a chronic and relapsing heterogenous autoimmune disease that primarily affects women of reproductive age. Genetic and environmental risk factors are involved in the pathogenesis of SLE, and susceptibility genes have recently been identified. However, as gene therapy is far from clinical application, further investigation of environmental risk factors could reveal important therapeutic approaches. We systematically explored two groups of environmental risk factors: chemicals (including silica, solvents, pesticides, hydrocarbons, heavy metals, and particulate matter) and drugs (including procainamide, hydralazine, quinidine, D-penicillamine, isoniazid, and methyldopa). Furthermore, the mechanisms underlying risk factors, such as genetic factors, epigenetic change, and disrupted immune tolerance, were explored. This review identifies novel risk factors, and their underlying mechanisms. Practicable measures for the management of these risk factors will benefit SLE patients and provide potential therapeutic strategies.