Increasing evidence link nanomaterials with adverse biological outcomes and due to the variety of applications and potential human exposures to nanoparticles, it is thus important to evaluate their toxicity for the risk assessment of workers and consumers. It is crucial to understand the underlying mechanisms of their toxicity as observation of similar effects after different nanomaterial exposures does not reflect similar intracellular processing and organelle interactions. A thorough understanding of mechanisms is needed not only for accurate prediction of potential toxicological impacts but also for the development of safer nanoapplications by modulating the physicochemical characteristics. Furthermore biomedical applications may also take advantage of an in depth knowledge about the mode of action of nanotoxicity to design new nanoparticle-derived drugs. In the present manuscript we discuss the similarities and differences in molecular pathways of toxicity after carbon black (CB) and titanium dioxide (TiO2) nanoparticle exposures and identify the main toxicity mechanisms induced by these two nanoparticles which may also be indicative for the mode of action of other insoluble nanomaterials. We address the translocation, cell death induction, genotoxicity, and inflammation induced by TiO2 and CB nanoparticles which depend on their internalization, reactive oxygen species (ROS) production capacities and/or protein interactions. We summarize their distinct cellular mechanisms of toxicity and the crucial steps which may be targeted to avoid adverse effects or to induce them for nanomedical purposes. Several physicochemical characteristics could influence these general toxicity pathways depicted here and the identification of common toxicity pathways could support the grouping of nanomaterials in terms of toxicity.