Although cumulative evidence suggests that a genetic predisposition pl
ays a major role in the development of systemic lupus erythematosus (S
LE), the susceptibility genes are mostly unknown. The difficulty in id
entifying susceptibility genes is due in part to the inherent nature o
f this polygenic complex disease and the diverse genetic backgrounds o
f human populations. Murine SLE models that have homogenous genetic ba
ckgrounds are less complex for genetic dissection. Genome-wide Linkage
studies of murine SLE have mapped the position of a number of suscept
ibility loci. Recently, several of these major murine loci have been s
hown to Link to different clinical and laboratory features of lupus-li
ke phenotypes. In addition, evidence for additional genetic contributi
ons via interaction between murine loci has been reported. In human SL
E, many polymorphic genes (which have potential roles in SLE, as sugge
sted by their known functions) have been associated with SLE or SLE su
bsets by population-based case-control or within-case studies. Because
more compelling genetic evidence includes linkage analysis, our group
has used the identified murine susceptibility loci as a guide and con
ducted linkage analysis of genetic markers located within a specific,
possibly syntenic human chromosomal region. Evidence for linkage of a
chromosome lq41-42 region was observed in SLE-affected sibling pairs f
rom multi pie ethnic groups. This article summarizes recent developmen
ts and outlines possible future directions in delineating the genetic
basis of SLE.