--- - |2 We performed a systematic review of genome‐wide gene expression datasets to identify key genes and functional modules involved in the pathogenesis of systemic lupus erythematosus (SLE) at a systems level. Genome‐wide gene expression datasets involving SLE patients were searched in Gene Expression Omnibus and ArrayExpress databases. Robust rank aggregation (RRA) analysis was used to integrate those public datasets and identify key genes associated with SLE. The weighted gene coexpression network analysis (WGCNA) was adapted to identify functional modules involved in SLE pathogenesis, and the gene ontology enrichment analysis was utilized to explore their functions. The aberrant expressions of several randomly selected key genes were further validated in SLE patients through quantitative real‐time polymerase chain reaction. Fifteen genome‐wide gene expression datasets were finally included, which involved a total of 1,778 SLE patients and 408 healthy controls. A large number of significantly upregulated or downregulated genes were identified through RRA analysis, and some of those genes were novel SLE gene signatures and their molecular roles in etiology of SLE remained vague. WGCNA further successfully identified six main functional modules involved in the pathogenesis of SLE. The most important functional module involved in SLE included 182 genes and mainly enriched in biological processes, including defense response to virus, interferon signaling pathway, and cytokine‐mediated signaling pathway. This study identifies a number of key genes and functional coexpression modules involved in SLE, which provides deepening insights into the molecular mechanism of SLE at a systems level and also provides some promising therapeutic targets. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8815-8825, November 2018.