The increasing use of engineered nanomaterials (ENMs) raises questions regarding their environmental impact. Improving the level of understanding of the genetic and molecular basis of the response to ENM exposure in biota is necessary to accurately assess the true risk to sensitive receptors. The aim of this Review is to compare the plant response to several metal-based ENMs widely used, such as quantum dots, metal oxides, and silver nanoparticles (NPs), integrating available "omics" data (transcriptomics, miRNAs, and proteomics). Although there is evidence that ENMs can release their metal components into the environment, the mechanistic basis of both ENM toxicity and tolerance is often distinct from that of metal ions and bulk materials. We show that the mechanisms of plant defense against ENM stress include the modification of root architecture, involvement of specific phytohormone signaling pathways, and activation of antioxidant mechanisms. A critical meta-analysis allowed us to identify relevant genes, miRNAs, and proteins involved in the response to ENMs and will further allow a mechanistic understanding of plant-ENM interactions.