Although most experimental data suggest that exposure to nanomaterials may be dangerous, the matter of their toxicity in humans is still unresolved. A key question is whether they may be more toxic than their bulk counterpart. To clarify this issue, we perform an in-depth analysis of size-related toxicological properties and discuss the pathogenetic pathways activated by oxidative and non-oxidative stress. In addition, new insights on the complex molecular inter-relationships arising from 'omics' are examined, in light of the information they can provide on specific intracellular events elicited by nanomaterials. Finally, we describe the mechanism of action of fibre-like nanomaterials. © 2014 Woodhead Publishing Limited. All rights reserved.