<p>Development of innovative strategies for detoxification of pesticides accumulated in ecosystems is of crucial importance for the global agricultural intensification and reducing their environmental footprint. One of the most promising approaches to the problem is the creation of synthetic microbial consortia possessing high catabolic activity and the ability to efficiently degrade persistent environmental pollutants. This review analyzes recent advancements in metagenomics that enable a detailed examination of the genetic diversity and functional potential of natural microbiomes. Special attention is given to the engineered modification of key genetic elements responsible for pesticide degradation, as well as synthetic biology methodologies aimed at the targeted construction of microbial consortia with predefined biodegradative properties. Additionally, the review discusses critical aspects of biosafety, biostability, and regulatory constraints associated with the introduction of genetically modified microbial systems into natural and agricultural ecosystems. The significance of an interdisciplinary approach is emphasized for the development of environmentally safe, adaptive, and highly effective biotechnological solutions. The implementation of such innovative strategies has the potential not only to minimize pesticide-related environmental burdens but also ensure the long-term sustainability of agricultural ecosystems. Furthermore, this review proposes conceptual models of semisynthetic and synthetic microbial consortia designed for the sequential degradation of chlorpyrifos and methyl parathion. These models are based on recent experimental advancements in metagenomics and synthetic biology, underscoring their potential for the development of novel biodegradation systems.</p>