Organisms adapt to their environment through different pathways involving communication between external stressors and internal biological pathways. In vertebrates, xenobiotics are detected, metabolized and eliminated through the inducible xenobiotic-metabolizing pathways (XMP). In this chapter, we will discuss the impacts of the chemical exposome complexity on the balance between detoxication and side effects. We will focus on the mechanisms of adaptation to chemical insults in mammals with a focus on xenobiotics detection and metabolism, using the biological pathway of the dioxin receptor AhR as an example. This pathway is involved in xenobiotic detection and elimination but it has been shown lately that it was involved in several other functions involving endogenous molecules, dietary substances and microbial metabolites. The large number of ligands of this receptor (often referred to as its promiscuity) and its role in critical physiological functions may account for the toxicity of several of its ligands. Another example that illustrates the balance between detoxication and hazardous effects is that of the adipose tissue which can store persistent pollutants, thereby protecting other tissues, but which also constitutes an internal source of those pollutants leading to chronic exposure.