Organophosphate cholinesterase inhibitors (OPs) are a family of potent neurotoxic chemicals that includes nerve agents and pesticides. Accidental or intentional exposures to OPs account for millions of poisoning cases each year. Adverse neurobehavioral outcomes from repeated low-level and acute high-level OPs exposures have been consistently observed in epidemiological studies. Repeated exposures to levels of OPs below the threshold for acute cholinergic toxicity (such as occupational exposures) have been linked to impaired neurobehavioral performance, including memory deficits. Despite the fact that the canonical mechanism of OP neurotoxicity is inhibition of acetylcholinesterase (AChE), there is limited epidemiological or experimental evidence linking AChE inhibition to neurobehavioral outcomes caused by repeated low-level OP exposures, and the mechanism(s) that mediate the neurotoxic effects of these exposures remain speculative. For acute OP exposures, current standard of care treatment is effective in reducing mortality, but unless administered within minutes of exposure, does not effectively protect against delayed brain damage and long-term morbidity, including altered brain structure, abnormal electrographic activity and impaired cognitive behavior. The pathogenic mechanism(s) that link the acute OP intoxication to delayed and persistent neurological sequelae are not well established.This dissertation seeks to address the functional role(s) of non-cholinergic mechanisms in OP neurotoxicity by applying two different adult rat models of OP exposures: 1) a rat model of occupational exposure to the OP pesticide chlorpyrifos (CPF); and 2) a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Chapter 2 demonstrates that repeated CPF exposure for 21 days caused sustained AChE inhibition, significantly impaired learning and memory, and increased biomarkers of oxidative stress and astrogliosis. Treatment with the antioxidant Trolox not only reduced expression of biomarkers of oxidative stress but also decreased astrogliosis and restored cognitive function in CPF-exposed rats. However, Trolox had no effect on CPF-induced AChE inhibition. These findings suggest a causal relationship between oxidative stress and cognitive impairment caused by occupational CPF exposure. In chapter 3, we investigated whether acute DFP intoxication promotes the development of cellular senescence, which has been linked to behavioral deficits associated with aging and neurodegenerative disease, but not yet examined in acute OP intoxication. Our data indicated that acute intoxication with DFP upregulates expression of the senescence biomarker, p16, exclusively in neurons, with neuronal p16 expression first observed at 3 and 6 months post-DFP intoxication in hippocampus and thalamus only. The spatiotemporal profile of neuronal p16 expression was significantly correlated with FJC labeling of degenerating neurons in these same brain regions and time points. These data identify cellular senescence as a potential mechanism contributing to the chronic neurologic sequelae of acute OP intoxication. The diverse range of adverse outcomes induced by OP neurotoxicity is highly dependent on the exposure paradigm and may involve mechanisms independent of AChE inhibition. Future studies are warranted to further understand the causal roles of non-cholinergic mechanisms in long-term neurological consequences following OP exposures and to identify therapeutic windows to provide optimal neuroprotection or prevention. The diverse range of adverse outcomes induced by OP neurotoxicity is highly dependent on the exposure paradigm and may involve mechanisms independent of AChE inhibition. Future studies are warranted to further understand the causal roles of non-cholinergic mechanisms in long-term neurological consequences following OP exposures and to identify therapeutic targets and windows to optimally preserve brain function in individuals intoxicated with OPs.