Organophosphorus (OP) pesticide poisoning causes significant morbidity and mortality, particularly in the developing world, with upwards of 3 million people poisoned each year. Although OP poisoning is not common in developed countries, recently greater attention has been given to these chemicals because of their similarity to chemical warfare agents. Despite the agricultural use of OP pesticides for roughly 60 years, no new therapies have been developed since the 1960s. A promising field of novel antidotes for OP poisoning, OP hydrolases, has recently garnered increased support. These bacterial enzymes have demonstrated tremendous prophylactic and antidotal efficacy against a few different OP classes in animal models. These studies, as well as the limitations and challenges of therapeutic development of these enzymes, are discussed.