The biological effects of engineered nanoparticles are presently a focus of interest in chemistry, biology, pharmacology, clinical medicine, and toxicology due to the enormous therapeutic and diagnostic potential that the particulate nature of nanoparticles offers for selective drug delivery and controlled release. This raises unprecedented safety issues, calling for novel paradigms to face the biocompatibility analysis of particulate (as opposed to molecular) bioactive agents that vary in shape, surface, and charge, in addition to chemical structure. This issue of MRS Bulletin focuses on the bioeffects of metal oxide nanostructures, whose high bioactivity can be exploited to design novel multifunctional devices for nanomedical applications, some of which are already undergoing testing in anticancer and antioxidant clinical trials. The ubiquitous application in research and technology of these non-biodegradable structures has evoked concerns regarding their potential hazards, due to the same chemical activities that promise nanomedical developments. A Janus-type scenario is emerging, pointing to intricate networks of beneficial and detrimental effects following the biological interactions of metal oxide nanoparticles.