The worldwide use of pesticides has great benefits for agriculture. Pesticides offer crop protection from pests, enhance crop yields, and preserve the quality of agricultural products during storage, transport, and commercialization, generating great economic benefits for farmers. However, the extensive use of pesticides in agricultural activities is related to severe environmental pollution, mainly in soil and water bodies, constituting a menace to biodiversity, soil fertility, food supply, and human health. The use of biological systems such as microorganisms has been proposed as an effective approach to mitigate pesticide-related environmental pollution. Establishing effective pesticide bioremediation strategies requires considering important aspects of microbial physiology as well as deep knowledge of the cellular processes, enzymes, and metabolic pathways that drive the pesticide degradation process in microorganisms. Modern research technologies, like genomics, transcriptomics, proteomics, and metabolomics, have been applied to studying microorganisms involved in pesticide bioremediation. The present chapter describes relevant research on the use of OMIC approaches during pesticide microbial degradation. The analysis of this information gives us an overview of the pesticide biodegradation mechanisms, such as the cellular strategies employed by microorganisms to counteract the stress and cellular damage caused by pesticide exposure and the molecular mechanisms (genes, enzymes, metabolites) involved in pesticide degradation. The information generated from multi-omics approaches is very useful for establishing more effective pesticide bioremediation strategies.