Although it is well known that genetic factors contribute significantly to the expression of systemic lupus erythematosus (SLE) it was only recently realized, through genome-wide searches, that the number of involved genes is rather large. The published information hints at two facts: first, the number of genomic loci identified in various diverse cohorts is large and not necessarily overlapping; and second, certain loci may be preferentially linked with specific clinical manifestations. The latter may ultimately lead to a better understanding of the nature of the clinical entity that we know as SLE, and identification of groups of patients prone to respond better to treatment or to develop significant adverse effects. Advances attained regarding the nature of the biochemical and molecular defects that underwrite the aberrant function of immune cells parallel the progress made on the genetic origin of the disease. The genetic links need to be connected with aberrant function of their products to validate their significance. It is expected that correction of molecular aberrations either medicinally or by gene therapy will provide the needed specific treatment for patients with SLE.