The report by the National Research Council of the US National Academy of Sciences, Toxicity Testing in the 21st Century: A Vision and a Strategy, has prompted a discussion about renewing regulatory toxicology - especially for chemicals - by harnessing in vitro tests, in silico approaches, and testing in lower organisms. The key change is basing the assessments on mechanisms and toxicant modes of action. Identifying pathways of toxicity (PoT), especially on a larger scale, evidently requires omics technologies. When the PoT is known, a test battery allowing higher throughput than the current approach can be constructed. Here, we propose an extension of this concept to mapping the entirety of PoT in humans: the human toxome. Mapping the human toxome will allow us, for the first time, to conclusively identify substances as nontoxic or to identify nontoxic concentrations of substances (i.e., concentrations at which no relevant PoT are triggered). The concept is explained, and opportunities and obstacles are discussed, aiming to promote an initiative which will form the core of a Human Toxicology Project to implement Toxicology for the 21st Century.