The manufactured nanomaterials (NMs) have specific physicochemical properties that confer unique mechanical, optical, electrical and magnetic characteristics that are beneficial for biomedical and industrial applications. However, recent studies have suggested that such specific physicochemical properties of the NMs may define nano-bio interactions thereby determining their toxic potential.One of the major concerns about NMs is the potential to induce cancer, suggested by some experimental studies, as seen for titanium dioxide nanomaterials or carbon nanotubes. To analyze in a short term the carcinogenic properties of a compound, genotoxicity assays in mammalian cell lines or animal models are frequently used. However, the investigation of the genotoxic properties of NMs has been inconclusive, up to date, since divergent results have been reported throughout the literature. While trying to understand how the NMs' characteristics may encompass increased toxicological effects that harbor uncertainties for public health, the use of correlation analysis highlights some physicochemical properties that influence the genotoxic potential of these NM.In this chapter, it is hypothesized that the different genotoxicity observed in closely related NMs may be due to subtle differences in their physicochemical characteristics. The present work provides an overview of the studies exploring the correlation between physicochemical properties of nanomaterials and their genotoxic effects in human cells, with focus on the toxicity of two groups of NMs, titanium dioxide nanomaterials and multiwalled-carbon nanotubes. It is suggested that, for tackling NMs' uncertainties, the in-depth investigation of the nano-bio interactions must be foreseen, where in vitro research must be integrated with in vivo and biomonitoring approaches, to cope with the complex dynamic behaviour of nanoscale materials.