The explosive growth of nanotechnology has brought challenging innovations in the synthesis of multifunctional nano-objects able to revolutionize the field of diagnosis and therapy in medicine. Furthermore, one important input of today's nanotechnology in biology is that their design will also allow real progress to achieve temporal and spatial site local therapy and imaging. Such a breakthrough is made possible by the development of multifunctional biocompatible nanosystems resulting from cutting-edge researches based on pluridisciplinary approaches. Among the challenges are the design of the organic coating and its grafting at the surface of NPs while preserving the properties of both NPs and molecules. The molecules should ensure the colloidal stability of NPs in physiological media, their biocompatibility and biodistribution, and may bear functions to couple bioactive groups. This paper aims at providing challenges in functionalization of iron oxide nanoparticles for biomedical applications. © 2015 by De Gruyter 2015.