A battery of short-term in vitro assays and/or in vivo protocols to evaluate single-agent mutagenicity and/or genotoxicity is available. However, a protocol to assess the effect(s) of complex mixtures in vivo following a positive test finding in vitro remains difficult. Complex interactions may occur in vivo because component pharmacokinetics increases the unpredictability of pharmacodynamic outcomes. The question arises as to whether in vitro mutagenic component(s) of a complex mixture, probably unidentified, reach target organ(s) in vivo at a sufficient concentration. To address the issue of an in vitro positive, standard in vivo chromosome damage assays to test both mixtures and fractions could be conducted but, to assess site-of-contact effects, the alkaline single cell-gel electrophoresis (“comet”) assay or DNA reactivity (e.g., 32P-postlabelling of DNA adducts) might be employed. A newer approach may be the derivation of a “biochemical-cell fingerprint” of potential target sites using infrared microspectroscopy. There is interest in platforms such as gene expression, proteomics, epigenomics or metabolomics as biomarkers of signature genotoxic or non-genotoxic mechanisms. One still needs to address whether a mutagenic and/or genotoxic component reaches a target organ. An approach to track levels of target-organ exposure may be to radio-label components with a short-lived positron-emitting radionuclide. The parent compound retains its physicochemical properties whilst allowing non-invasive in vivo tissue-specific imaging. However, determining target-organ concentration(s) and effect(s) in vivo remains a difficult challenge.