The derivation of pluripotent embryonic stem (ES) cell lines has opened up new areas of research in basic and applied science, most significantly in developmental biology and regenerative medicine. While application-oriented research has for the most part focussed on obtaining differentiated, organotypic cells from ES cells for future cell grafting therapies, ES cells have more immediate potential for use in toxicological in vitro assays used during drug development. ES cells are derived from blastocyst-stage embryos and offer an in vitro model for early development, thus enabling tests for teratogenicity testing in a human cell culture system and avoiding the pitfalls of inter-species differences. Differentiated, organotypic cells obtained from ES cells can potentially replace the primary cells and cell lines currently used for in vitro toxicology by offering a more consistent and potentially limitless source of differentiated cells. This can facilitate the establishment of comprehensive toxicogenomics and -proteomics databases and complement current databases that rely on data obtained from animal experiments. More recently, induced pluripotent stem (iPS) cells with ES cell-like properties have been obtained through reprogramming of somatic cells, thus enabling the generation of disease-specific cell lines. We review the potential of combining ES cells and ES cell-derived somatic cells with “omics” technologies for in vitro toxicology with a particular emphasis on the development of toxicogenomics and toxicoproteomics signatures. A separate section describes the potential of iPS cells for toxicology.