The article explores the extensive post-transcriptional regulation of microRNAs (miRNAs) and its implications for cancer. The authors show that a significant fraction of miRNA genes are regulated at the Drosha processing step, which is crucial for miRNA maturation. During early mouse development, many miRNA primary transcripts, including the Let-7 family, are highly expressed but not processed by Drosha. This regulation is not observed in other organisms, such as *C. elegans*, where let-7 is continuously expressed throughout development. The study also reveals that the widespread down-regulation of miRNAs in cancer is due to a failure at the Drosha processing step, suggesting a novel mechanism for miRNA down-regulation in cancer. The findings highlight the importance of post-transcriptional regulation in miRNA function and provide insights into the molecular mechanisms underlying miRNA expression changes in cancer.The article explores the extensive post-transcriptional regulation of microRNAs (miRNAs) and its implications for cancer. The authors show that a significant fraction of miRNA genes are regulated at the Drosha processing step, which is crucial for miRNA maturation. During early mouse development, many miRNA primary transcripts, including the Let-7 family, are highly expressed but not processed by Drosha. This regulation is not observed in other organisms, such as *C. elegans*, where let-7 is continuously expressed throughout development. The study also reveals that the widespread down-regulation of miRNAs in cancer is due to a failure at the Drosha processing step, suggesting a novel mechanism for miRNA down-regulation in cancer. The findings highlight the importance of post-transcriptional regulation in miRNA function and provide insights into the molecular mechanisms underlying miRNA expression changes in cancer.