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As one member of the heterogeneous ribonucleoprotein (hnRNP) family, scaffold attachment factor A (SAF-A) or hnRNP U, is an abundant nuclear protein. With RNA and DNA binding activities, SAF-A has multiple functions. The present review focused on the biological structure and different roles of SAF-A and SAF-A-related diseases. It was found that SAF-A maintains the higher-order chromatin organization via RNA and DNA, and regulates transcription at the initiation and elongation stages. In addition to regulating pre-mRNA splicing, mRNA transportation and stabilization, SAF-A participates in double-strand breaks and mitosis repair. Therefore, the aberrant expression and mutation of SAF-A results in tumors and impaired neurodevelopment. Moreover, SAF-A may play a role in the anti-virus system. In conclusion, due to its essential biological functions, SAF-A may be a valuable clinical prediction factor or therapeutic target. Since the role of SAF-A in tumors and viral infections may be controversial, more animal experiments and clinical assays are needed. [ABSTRACT FROM AUTHOR]