The aim of this original review is to highlight and analyze the most recent progress and challenges in the synthesis and surface modifications of superparamagnetic iron oxide (FeO) nanoparticles (NPs) for multimodal imaging and therapy applications, which represent important fields in medicine in general and cancer in particular. Thus, the oncology domain is rapidly moving to a more personalized medicine including precision imaging and theranostic approaches. Novel biocompatible FeO nanoparticulate systems have been designed for enhanced and targeted cellular uptake by surface layer coating modifications, to have improved r relaxivity for sensitive magnetic resonance (MR) imaging applications, to have the ability to be used for dual mode imaging, and to be used for imaging-guided cancer therapy. In this review, we analyzed in depth the new strategies for generating biocompatible multifunctional FeO nanoplatforms for both the diagnosis and therapy of cancer.