In this study, Jones et al. investigated the biological role of miRNA regulation by target-directed microRNA degradation (TDMD) in mammals using mice with constitutive or conditional deletion of Zswim8, an essential TDMD factor, and provided new insight into the role of TDMD in embryonic organogenesis, particularly that of the heart and lungs. They further comprehensively profiled TDMD-regulated miRNAs across various embryonic tissues and provide insights into TDMD features of miRNA regulation, such as tissue-specific arm switching, tailing, trimming, and clustered transcription, during embryonic development.