Many environmental chemicals can alter cellular homeostasis by stimulating or inhibiting various molecular pathways. Determination of which compounds are active and how they function is key to understanding the total adverse health effects possessed within our environment. Much of the research done on xenobiotics has focused on the ability of select compounds to mimic the endogenous hormone estrogen by binding to and activating the estrogen receptors (ERs) and thereby producing estrogenic effects. However, recent evidence suggests these compounds may affect other cellular pathways. I hypothesized the persistent pesticide dichlorodiphenyltrichloroethane (DDT) can induce gene expression through non-ER-mediated mechanisms. Here, I demonstrate DDT and its metabolites stimulate activator protein-1 (AP-1)-mediated gene expression through an ER-independent mechanism. DDT treatment increases AP-1 activity by inducing a shift to a more active conformation of AP-1. Since AP-1 is a known target of mitogen-activated protein kinase (MAPK) signaling, I sought to determine a role for the MAPKs in DDT-induced AP-1 activity. The ability of DDT and its metabolites to stimulate AP-1 is dependent on the p38 MAPK signaling pathway. I also demonstrate however, DDT-induced p38 potentiates other transcription factors. Thus, I explored the possibility that p38 could be targeting more general transcriptional regulators. Active p38 phosphorylates and potentiates the transcriptional coactivators CREB-binding protein (CBP), p300, and glucocorticoid receptor interacting protein 1 (GRIP I), and hence can affect a range of transcription factors and target multiple response elements. Since (1) p38 is a stress kinase and has been associated with induction of apoptosis and (2) there are multiple AP-1-like sites located in the promoters of different cell death receptors. I further hypothesized DDT induces apoptosis in cells through the expression of select death receptors. As a biological endpoint, I show DDT-induced p38 activity increases tumor necrosis factor-alpha (TNF-alpha) expression and ultimately apoptosis through a pathway involving the mitochondria. We still know little about the activity of compounds we put into the environment 70 years ago. Taken together, these data represent a novel environmental signaling mechanism induced by DDT and its metabolites. The knowledge of this pathway will help us prevent the production of harmful pollutants in the future