Nanotechnology has given scientists new tools for the development of advanced materials for the detection and diagnosis of various types of diseases. In particular, ultrasmall superparamagnetic iron oxides (USPIOs) have been investigated in many biological applications, both in vitro and in vivo. Due to their small size (diameter < 20 nm), these particles are not immediately removed from the circulation by the reticuloendothelial system (RES), have a longer blood half-life, a wider biodistribution and allow potential targeting with appropriate bioconjugates to specific tissues both normal and tumorous. This review will mainly discuss the synthesis of USPIOs and their applications as MRI contrast agent for disease detection.