The widespread use of pesticides in modern agriculture is of increasing concern due to environmental contamination and subsequent biodiversity loss. Chlorpyrifos is a toxic organophosphate pesticide. Repeated applications of chlorpyrifos modify the soil microbial community structure and pose potential health risks to the other nontargets. Chlorpyrifos has been reported as the second most commonly detected pesticide in food and water. Extensive use of chlorpyrifos in agriculture and persistence in the environment have raised public concern and demand for safe technologies to overcome the pollution and toxicity problems. Here, we review pollution and toxicity issues associated with chlorpyrifos use and discuss strategies to solve pesticide contamination. Chlorpyrifos, previously shown to be resistant to enhanced degradation, has now been proved to undergo enhanced microbe-mediated decay. Here, special emphasis is given to degradation methods such as ozonation, Fenton treatment, photodegradation, and advanced oxidation processes along with microbial degradation. Finally, we focus on degradation process at enzyme and molecular levels which will enable us to elucidate the exact degradative pathway involved in biodegradation.