In this paper, we reviewed the data on the use of HepG2 cells to detect cytoprotective, antigenotoxic and cogenotoxic agents. Owing to their intact and inducible phase I and phase II enzymes, HepG2 cells are able to activate and detoxify xenobiotics and therefore reflect the metabolism of xenobiotics in the human body better than other metabolically incompetent cells used in conventional in vitro assays. Several dietary and non-dietary agents were found to be protective against different groups of cytotoxic and DNA-damaging xenobiotics in HepG2 cells and the mechanism of protection includes scavenging of electrophiles, reactive oxygen species and peroxides, inhibition of phase I activating enzymes, induction of phase II detoxifying enzymes and interactions with DNA-repair and/or replication processes. Additionally, certain non-mutagenic substances were found to enhance the effect of genotoxic agents in HepG2 cells by increasing the metabolic activation of the latter. In conclusion, HepG2 cells are of great relevance to detect cytotoxic and genotoxic substances and by extension cytoprotective, antigenotoxic and cogenotoxic agents.