The essence of nanotechnology is the production of nanoparticles (NPs) with unique physicochemical properties allowing worldwide application in new structures, materials, and devices. The consequently increasing human exposure to NPs has raised concerns regarding their health and safety profiles. Titanium dioxide (TiO2) has been reported to induce adverse pulmonary responses in exposed animals. However, the potential more dangerous biological activities of TiO2 NPs compared to their fine-sized counterparts are not fully understood. Therefore, this work is aimed to provide a comprehensive evaluation of the toxic effects induced by TiO2 NPs in in vivo experiments. It is intended to deeply understand the toxicological behaviour of TiO2 NPs and to predict potential human health effects. Moreover, it may be an instrument to extrapolate relevant data for human risk evaluation and management and to identify those critical aspects that deserve great attention in future population and epidemiologic research.