Ocean-related activities are increasing every day and the successive build-up of organisms on the ship hulls (marine biofouling) leads to higher heavy oil consumption which incurs in increased costs and emissions of polluting gases contributing to acceleration of greenhouse and acid rain effects. Other major ecological consequence of marine biofouling on the ship hulls is the marine biodiversity decline due to the trans-global contamination of ecosystems with non-indigenous species. On the other hand, antifouling paints in use are continuing leaching persistent, bioaccumulative and toxic substances to the oceans and the marine industry is facing the phase-out of most of the current biocide-based coatings, shortening the available alternatives. Climate changes and oceans temperature raising are changing the dynamic of species, also creating new challenges to combat marine biofouling. Therefore, the development of harmless and effective antifouling systems to prevent the marine biofouling is an urgent demand. The Natural Products and Medicinal Chemistry Group of CIIMAR has been synthesizing several antifouling (AF) compounds and applying the same principles of Drug Discovery process: high throughput screening to discover hits, lead generation after some optimization of hit compounds, and finally lead optimization. If this approach is followed, it is highly probable that the necessary balance between the feasible synthesis, antifouling potency, low toxicity and bioaccumulation will be found. From this work, it is possible to conclude that the application of Medicinal Chemistry principles to solve environmental problems becomes an extremely useful tool and fulfills the broad sense of the concept of this scientific area.