Systemic lupus erythematosus (SLE; OMIM 152700) is a highly heterogeneous disorder, characterized by differences in autoantibody profile, serum cytokines, and a multi-system involvement commonly affecting the skin, renal, musculoskeletal, and hematopoetic systems clinical manifestations involving. Disease features range from mild manifestations, such as rash or arthritis, to life-threatening end-organ manifestations, such as glomerulonephritis or thrombosis, and it is difficult to predict which manifestations will affect a given patient. SLE is caused by interactions between susceptibility genes and environmental factors resulting in an irreversible loss of immunologic self-tolerance. Incidence is highest in women during the reproductive years; however, people of all ages, genders, and ancestral backgrounds are susceptible. A striking 9:1 female to male differential appears in incidence, which remains largely unexplained. However, people of both sexes and all ages and ethnic backgrounds are susceptible. Distinct differences regarding the pathogenesis of SLE between patients of different ancestral backgrounds have been observed so far, including differences in specific clinical manifestations, disease-susceptibility genetic variants and IFN levels. Genome-wide association studies (GWAS) have attempted to elucidate partially the complex genetic architecture of SLE and to point out the existing differences in risk variants across different continental populations, considering that some alleles have not been found in all ancestral backgrounds. Levels of circulating IFN-α is a heritable risk factor in SLE with causal role in pathogenesis, they differ between SLE patients from different ancestral backgrounds and this information could be important as therapeutics is developed to target this pathway. This review highlights some recent findings referred to the multilevel differences appearing in SLE patients from different ancestral backgrounds and further understanding of this knowledge may permit the development of personalized treatments based on patients' ancestry.