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The protein expression of gelsolin, an actin scavenger controlling cytoskeletal remodeling, cell morphology, differentiation, movement, and apoptosis, has been found to be significantly decreased in several pathological conditions including neurodegenerative diseases, inflammatory disorders, and cancers. Its extracellular isoform, called plasma gelsolin (pGSN), is one of the most abundant plasma proteins in the circulation, and has emerged as a novel diagnostic biomarker for early disease detection. Current evidence reveals that gelsolin can function as either an oncoprotein or a tumor suppressor depending on the carcinoma type. Interestingly, recent studies have shown that pGSN is also involved in immunomodulation, revealing the multifunctional roles of pGSN in tumor progression. In this review, we discuss the current knowledge focusing on the roles of gelsolin in inflammation and wound healing, cancers, and tumor microenvironment. Future prospects of pGSN related studies and clinical application are also addressed.