Susceptibility to systemic lupus erythematosus (SLE) depends on genetic and environmental factors. Genome scan studies have identified eight chromosomal regions with significant linkage to SLE that are confirmed by individual cohorts, suggesting that susceptibility genes may be identified within each of these loci. Linkage studies and single nucleotide polymorphisms (SNPs) have led to the identification of positional candidate genes, and their functional allelic variants have demonstrated molecular pathogenesis of the disease. The discovery of positional candidate genes that are associated with various autoimmune diseases signifies a common pathway in the mechanism of these diseases. Copy polymorphisms in susceptibility genes provide evidence in how genetic plasticity affects complex phenotypes as seen in SLE.