Dysregulation of gene expression can cause complex disease phenotypes. MicroRNAs (miRNAs) are well known to fine-tune cellular gene expression to control immune cell development and regulate adaptive and innate immune responses. Discoveries over the past decade have indicated that aberrant expression of miRNAs is associated with the pathogenesis of multiple immunological diseases, including systemic lupus erythematosus (SLE). Indeed, profiling miRNA expression in blood cells, body fluid and target tissues taken from patients with SLE has revealed unique miRNA signatures when compared with healthy individuals or those with other diseases. Moreover, dysregulation of these miRNAs has also been found to be associated with disease activity and major organ involvement. In our opinion, therefore, miRNAs have the potential to act as biomarkers for the diagnosis and assessment of patients with SLE. This Review provides an overview of the novel cellular and molecular mechanisms that seem to underlie the roles of miRNAs in SLE disease processes, as well as the future therapeutic potential of targeting miRNAs in the management of patients with SLE.