Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect almost any organ in the human body. Despite significant advancements in our understanding of SLE over the recent years, its exact mode of onset and disease progression remains elusive. Low concordance rates among monozygotic twins with SLE (as low as 24%), clustering of disease prevalence around polluted regions and an urban-rural difference in prevalence all highlight the importance of environmental influences in SLE. Experimental data strongly suggests a complex interaction between the exposome (or environmental influences) and genome (genetic material) to produce epigenetic changes (epigenome) that can alter the expression of genetic material and lead to development of disease in the susceptible individual. In this review, we focus on the available literature to explore the role of environmental factors in SLE disease onset and progression and to better understand the role of exposome-epigenome-genome interactions in this dreaded disease.