Cyclooxygenase-2(COX-2), an important inducible enzyme, can be induced by pro-inflammatory cytokines, tumor promoters, mitogens, and growth factors in a variety of cells, involving in many pathological processes, such as inflammation, cell proliferation, and apoptosis. This review focused on the relationship of COX-2 with endoplasmic reticulum stress and autophagy, describing the mechanisms of epigenetics and genetics mediated by microRNA and the single nucleotide polymorphism of COX-2 gene(PTGS2) in the injury and toxicity induced by environmental factors. This review provided insight of COX-2 as a molecular intervention target against the toxic injuries induced by environmental factors.