Apolipoprotein E (apoE) is a polymorphic protein encoded in chromosome 19. In humans, apoE exists primarily in three isoforms—apoE2, apoE3, and apoE4—and plays a key role in lipid transport in both plasma and the central nervous system. Importantly, the apoE has significant neurobiological functions, and apoE4 is the strongest genetic risk factor for the development of Alzheimer’s disease. This chapter explores how genetic factors like the APOE gene modulate responses to environmental toxicants. Specifically, it highlights the effects of pesticides, such as chlorpyrifos, along with particulate matter, heavy metals, and other contaminants like the flame-retardant BDE-209. Up-to-date literature results document that these environmental factors produce toxic effects that vary depending on APOE genotype, emphasizing the gene’s influence on toxicant susceptibility. Moreover, growing evidence suggests that epigenetic mechanisms, particularly DNA methylation, may regulate these gene-environment interactions. However, research on the epigenetic regulation of APOE in response to toxic exposure remains limited, highlighting the need for further studies in this area.