Over the past few decades, multiple mechanisms have emerged that operate to prune the lymphocyte repertoire of self-reactive specificities and maintain immunological tolerance. Multiple families of small noncoding RNAs known as microRNAs (miRNAs) target immune transcripts to fine-tune gene expression and turn on negative feedback loops. Both of these actions are crucial to limit co-stimulation, set precise cellular activation thresholds, curtail inflammation, control lymphocyte growth, and maintain regulatory T cell homeostasis and suppressive function. Analysis of predicted miRNA-mediated regulation of 72 lupus susceptibility genes in humans and mice reveals most contain numerous target sites for over 140 miRNAs conserved in mammals. MECP2, ROQUIN/RC3H1, BCL2, BIM, and PTEN contain over 50 miRNA target sites each, highlighting the need to control their final protein products with enormous precision to maintain the balance between immunity and tolerance. Overlap among targets of individual miRNAs is considerable, with each miRNA targeting a median of nine autoimmune genes. Three miRNAs--miR-181, miR-186, and miR-590-3p--together are predicted to target over 50 of all lupus genes. Also, a single miRNA cluster located at 14q32.31 containing 11 miRNAs is predicted to regulate 48 lupus susceptibility genes. Dysregulation of single or a few miRNAs or miRNA clusters can result from genetic variation, hormonal influences, or environmental triggers including EBV infection. In the light of this vast and promiscuous miRNA-mediated regulation of autoimmune genes it is anticipated that changes in miRNA levels or their target sequences will help explain susceptibility to complex autoimmune diseases.