It is acknowledged that the physicochemical properties of nanomaterials (NMs) have an impact on their toxicity and, eventually, their pathogenicity. These properties may include the NMs’ surface chemical composition, size, shape, surface charge, surface area, and surface coating with ligands (which can carry different functional groups as well as proteins). Nanotopography, defined as the specific surface features at the nanoscopic scale, is not widely acknowledged as an important physicochemical property. It is known that the size and shape of NMs determine their nanotopography which, in turn, determines their surface area and their active sites. Nanotopography may also influence the extent of dissolution of NMs and their ability to adsorb atoms and molecules such as proteins. Consequently, the surface atoms (due to their nanotopography) can influence the orientation of proteins as well as their denaturation. However, although it is of great importance, the role of surface topography (nanotopography) in nanotoxicity is not much considered. Many of the issues that relate to nanotopography have much in common with the fundamental principles underlying classic catalysis. Although these were developed over many decades, there have been recent important and remarkable improvements in the development and study of catalysts. These have been brought about by new techniques that have allowed for study at the nanoscopic scale. Furthermore, the issue of quantum confinement by nanosized particles is now seen as an important issue in studying nanoparticles (NPs). In catalysis, the manipulation of a surface to create active surface sites that enhance interactions with external molecules and atoms has much in common with the interaction of NP surfaces with proteins, viruses, and bacteria with the same active surface sites of NMs. By reviewing the role that surface nanotopography plays in defining many of the NMs’ surface properties, it reveals the need for its consideration as an important physicochemical property in descriptive and predictive toxicology. Through the manipulation of surface topography, and by using principles developed in catalysis, it may also be possible to make safe-by-design NMs with a reduction of the surface properties which contribute to their toxicity.