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Melanin is s most widely distributed pigment and is found in bacteria, fungi, plants, and animals. Melanogenesis is under complex regulatory control by multiple agents interacting through pathways activated by hormonal and receptor-dependent and -independent mechanisms. There are about 20 genes that are involved in the biochemical pathway of melanogenesis and its regulation, which include: tyrosinase, microphthalmia-associated transcription factor, melanocortin1 receptor, adenylate cyclase, protein kinase A. Human melanogenesis regulatory proteins such as MAPK1, CREB3, and CREBP, have binary interaction with the protein of herpesvirus, hepatitis C virus, Human immunodeficiency virus type 1, Simian virus 40, and Human adenovirus A and C. Melanin is a double-edged sword in host-pathogen interaction (e.g., human-bacteria and/or fungi interaction). The inducers of upregulation of melanogenesis include fluvoxamine, famotidine, terbutaline, heliotrine, sirolimus, dicoumarol, Prestwick-860, carbimazole, (-)-MK-801, rilmenidine, hydrastine hydrochloride, haloperidol, scopolamine N-oxide, raubasine, and dihydroergocristine. In melanogenesis, GSK3B, CSNK2A, MAPK1, MAPK3, MAPK14, ERK1, and HIPK2 were the major kinases, while RUNX1, GATA1, and REST, SUN12, and RCOR1 were the major transcription factors. This study has reviewed the melanogenesis pathway, its regulations as well as applications to viral infection. The antiviral activity of melanin and its complex in the presence of antibacterial and antifungal compounds should be investigated to further provide insight for biomedical, biotechnological, and pharmacological applications.