Abstract: Magnetic iron oxide nanoparticles (MIONs) have been widely used in biomedical fields, including targeted drug delivery, magnetic resonance imaging, separation and enrichment of cancer cells, and tumor-targeted therapy. However, MIONs are increasingly necessary to ensure reduced toxicity, more stable colloidal dispersion, better biocompatibility, and higher magnetic responsiveness. Thus, apart from the continuous improvement of material synthesis, specific surface modification of MIONs is essential to choose appropriate materials. This paper reviews the available methods and materials and their function in MION surface modification as well as their applications for the separation of circulating tumor cells.