Background: Mercury is a threat for the aquatic environment. Nonetheless, the entrance of Hg into food webs is not fully understood. Macrophytes are both central for Hg entry in food webs and are seen as good candidates for biomonitoring and bioremediation. Methods: We review the knowledge gained on the uptake and effects of inorganic Hg (IHg) and methyl-Hg (MMHg) in the macrophyte Elodea nuttallii found in temperate freshwaters. Results: E. nuttallii bioaccumulates IHg and MMHg, but IHg shows a higher affinity to cell walls. At the individual level, IHg reduced chlorophyll, while MMHg increased anthocyanin. Transcriptomics and metabolomics in shoots revealed that MMHg regulated a higher number of genes than IHg. Proteomics and metabolomics in cytosol revealed that IHg had more effect than MMHg. Conclusions: MMHg and IHg show different cellular toxicity pathways. MMHg's main impact appears on the non-soluble compartment, while IHg's main impact happens on the soluble compartment. This is congruent with the higher affinity of IHg with dissolved OM (DOM) or cell walls. E. nuttallii is promising for biomonitoring, as its uptake and molecular responses reflect exposure to IHg and MMHg. More generally, multi-omics approaches identify cellular toxicity pathways and the early impact of sublethal pollution.