Clinical and diagnostic laboratories often encounter patient sera containing antinuclear antibodies (ANAs) that produce a nuclear dense fine speckled immunofluorescence pattern on HEp-2 cells. These autoantibodies usually target the dense fine speckled protein of 70 kDa (DFS70), commonly known as lens epithelium-derived growth factor p75 (LEDGFp75). Anti-DFS70/LEDGFp75 autoantibodies have recently attracted much interest because of their relatively common occurrence in sera from patients with positive ANA tests with no clinical evidence of systemic autoimmune rheumatic disease (SARD). Their presence has been documented primarily in patients with diverse non-SARD inflammatory conditions and "apparently healthy" individuals. While there is circumstantial evidence that depending on the context these autoantibodies could play protective, pathogenic, or sensor roles, their significance remains elusive. DFS70/LEDGFp75 has emerged during the past decade as a stress transcription co-activator relevant to HIV integration, cancer, and inflammation. It is not clear, however, what makes this protein the target of such a common autoantibody response. We suggest that a better understanding of DFS70/LEDGFp75 biology is key to elucidating the significance of its associated autoantibodies. Here, we discuss briefly our current understanding of this enigmatic autoantigen and potential scenarios leading to its targeting by the immune system.