SummaryNovel therapeutic options are urgently needed to improve the global treatment of viral infections. Tripartite motif (TRIM) family proteins are involved in various biological and cellular functions including differentiation, development, proliferation, oncogenesis, innate immunity, and viral autophagy. Various TRIM proteins show antiviral properties against different viral infections and are now transitioning from ubiquitin proteins to an efficient and emerging therapeutic class of proteins. TRIM proteins combat viruses by targeting them at pre/post transcription levels. This review summarizes the comprehensive roles of different TRIM proteins along with their expression systems and their applications towards antiviral therapeutics.