From regulatory perspectives, there has been a debate in the scientific literature as to whether or not metallic engineered nanomaterials (ENMs) should be treated as new chemicals in terms of their toxic effects upon biological species. This debate has prompted us to examine the scientific evidence to validate those paradoxical claims. Investigations covering the effects of metallic ENMs and metal-based ions in the same study were included in this research. The findings reported herein suggest that the different arguments are valid if a wider perspective takes into account the common, different and unique effects of metallic nanoparticles versus metal-based ions. This perspective has been evident from investigations of aquatic (lower organisms such as Daphnia magna and higher organisms like zebra fish) and other organisms (e.g., microbes, nematodes, animal and human cells). It is suggested that the regulation of metallic nanomaterial-based products be transformed to a tier-based approach as a function of the common, different and unique effects to manage the complexity brought into light due to the infinite combinations of the particle physical–chemical properties.