One of the major success determinants in targeted in vivo drug delivery using SPIONs is the adequacy of magnetic gradient. This can be partially achieved by using superconducting magnets, local implantation of magnets and application of magnetic stents. Other issues that must be considered include the pharmacokinetics and in vivo fate of SPIONs, their biodegradability, biocompatibility, potential side effects and the crucial impact of protein corona on either drug release profile or mistargeting. Surface modification of SPIONs can open up the possibility of drug delivery to intracellular organelles, drug delivery across the blood-brain barrier, modifying metabolic diseases and a variety of other multimodal and/or theranostic applications.