Evolutionary processes have not yet developed specific and safe ways to detoxify all chemical species new to our environment. Indeed, some are transformed and/or conjugated by the liver into more toxic species. Environmental factors can modulate hepatic enzyme systems. Particularly responsive are the mixed function oxidases, which initiate the transformation of many xenobiotics to excretable species via reactions which generate electrophilic intermediates such as free radicals, epoxides and aldehydes. Unless these reactive metabolites are rapidly removed by subsequent detoxification reactions or by endogenous defense systems, destructive cytotoxic reactions can be triggered or cell constitutents "attacked" thereby causing either acute injury and/or more latent molecular injury to long chain biopolymers resulting in chromatin damage, or tumors. In vitro systems using purified, specialized cell fractions may be of considerable value in defining metabolic processes, but the results must be relevant to in vivo conditions. Although human liver is peculiarly resistant to tumorigenesis, liver microsomes (isolated endoplasmic reticulum) are extensively used as biological activators for in vitro mutagenicity test systems. The in vivo defense system of liver cells must be exceptionally efficient! Reactive metabolites generated in liver may be stable enough to migrate and cause injury to other tissues or organ systems. It is important to characterize metabolic pathways of toxic xenobiotics, subsequent molecular sites or modes of injury, and factors which depress or augment cellular defense systems including the biliary system responsible for the excretion of many xenobiotics. Only then can techniques or treatments be developed to screen individuals for risk to specific groups of xenobiotics, to protect those exposed, and to treat those injured.