The Red Sea represents a potential ecosystem with very rich biodiversity in the production of unique natural compounds. Recently, fungal secondary metabolites had been a major domain of research in the meadow of natural compounds with special emphasis on fungal strains isolated from marine ecosystems. More than 150 interesting secondary metabolites going with different classes of natural compounds had been reported with potential biological actions as cytotoxic activity with emphasis to the application of different approaches for example OSMAC ( one strain many compounds ) approach. The current review presents a comprehensive report for fungal secondary metabolites isolated from the Red Sea ecosystems either as endophytes from marine invertebrates (for example corals and sponges) and plants for example (algae and mangrove) or as free living strains collected from sea sediments from different locations of Red Sea. Different databases had been utilized including the EKB (Egyptian Knowledge Bank), SciFinder and MarinLit.. In no doubt, the richness of published data directs to the marine fungi's medicinal potential. It will continue to be challenging to incorporate marine fungus into traditional therapy. The clinical environment demonstration of therapeutic activity is a fundamental task for medicine research. For the profit of patients all through the world, it is to be wished that this significant barrier will be removed in the years to arise.