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 (Fe₃O₄) 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 Fe₃O₄ nanoparticulate systems have been designed for enhanced and targeted cellular uptake by surface layer coating modifications, to have improved r₂ 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 Fe₃O₄ nanoplatforms for both the diagnosis and therapy of cancer.