Long non-coding RNAs (lncRNAs) have emerged as key epigenetic regulators that govern gene expression and influence multiple biological processes. Accumulating evidence demonstrates that lncRNAs have critical roles in immune cell development and function. In this Review, the molecular mechanisms of gene expression regulation by lncRNAs are described and current knowledge of the role of lncRNAs in immune regulation and inflammation are presented, highlighting strategies for defining the roles of lncRNAs in the pathogenesis of multiple rheumatic diseases. Finally, research progress in understanding the role of lncRNAs in rheumatic diseases is discussed.