Heat shock proteins (HSPs) have been implicated in maintaining cellular homeostasis and survival. Xenobiotics pose stress to the exposed organisms at different levels of organization. To protect cellular homeostasis, organisms exert defense responses. One of the major cellular defense response pathways includes HSP. A plethora of studies have demonstrated the altered expression of HSP in different model systems against xenobiotic exposure. This chapter is intended to highlight the contribution/implication of HSP in xenobiotics-induced stress by reviewing the relevant toxicological studies in the past two decades. HSPs act as molecular chaperones, vital in maintaining cellular homeostasis under normal and pathophysiological conditions. A wide range of xenobiotics induces HSP expression in the exposed organisms. HSPs are implicated in toxicology as early indicators and modulators of xenobiotic-induced stress. This chapter has also discussed the implications/role of HSPs in maintaining cellular homeostasis and survival against xenobiotic stress. Relevant cited studies in this chapter are from the last two decades.