Circular RNAs (circRNAs) have been identified as important regulators in different developmental processes and disease pathogenesis. The loop structure of circRNAs makes them very stable in different conditions and microenvironments. circRNAs can affect microRNA (miRNA) and RNA binding protein (RBP) activity, encode functional proteins and regulate gene transcription. Recently, two circNFIX variants derived from the same gene, the Nuclear Factor I X (NFIX) gene, were determined as participants in the pathological processes of various diseases such as heart diseases and cancers. Both circNFIX variants are exonic circular RNAs and mainly function by sponging miRNAs. In this review, we summarize the current knowledge on circRNAs, elucidate the origins and properties of two circNFIX variants, explore the roles of two circNFIX variants in different diseases, and present clinical perspectives.