Firmly attached to different living or non-living, solid or fluid surfaces rich in nutrients and moisture, microbial biofilm is a matter of great interest due to its major importance for the healthcare community. Depending on common strategies such as mutual protection and hibernation (quiescent bacteria), the resistance, survival and virulence of microbial communities have large implications for human pathology, clinical environment and biomedical devices. The microbial biofilm is continuously changing, stimulating inflammation, increasing vascular permeability and preventing the action of macrophages. About 80% of human infections affecting the gastrointestinal, genitourinary and respiratory systems, oral mucosa and teeth, eyes, middle ear and skin are caused by biofilm-associated microorganisms. Therefore, the search for modern strategies is even more important as microbial biofilms resistant to conventional antibiotics, antiseptics and disinfectants are involved in the frequent treatment failures of some chronic inflammatory diseases and wounds. Natural products containing secondary metabolites, such as aromatic compounds, sulphurated derivatives, terpenoids (essential oils) and alkaloids as quorum-sensing inhibitors and biofilm disruptors, are promising alternatives for the prophylaxis and treatment of chronic infections. Surface modification of medical devices with non-polar functionalized nanoparticles stabilizes the natural compounds antibiofilm activity and inhibits microbial adhesion and biofilm formation and growth for a longer period of time. In this regard, an interdisciplinary approach is needed due to the large number of natural derivatives alone or in combination with biocompatible and biodegradable micro-/ nano-engineered materials.