An impressive development has been achieved toward the production of well-defined "smart" inorganic nanoparticles, in which the physicochemical properties can be controlled and predicted to a high degree of accuracy. Nanoparticle design is indeed highly advanced, multimodal and multitargeting being the norm, yet we do not fully understand the obstacles that nanoparticles face when used in vivo. Increased cooperation between chemists and biochemists, immunologists and physicists, has allowed us to think outside the box, and we are slowly starting to understand the interactions that nanoparticles undergo under more realistic situations. Importantly, such an understanding involves awareness about the limitations when assessing the influence of such inorganic nanoparticles on biological entities and vice versa, as well as the development of new validation strategies.