MicroRNAs (miRNAs) are conserved non-coding RNAs that regulate gene expression by targeting partially complementary sequences in the mRNAs. Each miRNA potentially regulates hundreds of mRNA targets, thus controlling a variety of biological processes, including mammalian cellular differentiation and development. In spite of widespread efforts to understand the roles of individual miRNAs little progress has been made towards unravelling the regulation of their biogenesis. My group has focused on elucidating the cis and trans-acting factors of tissue-specific miRNA biogenesis in mammalian cells. We have identified factors that regulate the production of brain-enriched and brain-specific miRNAs, as well as factors that are responsible for the selective uridylation and degradation of miRNA precursors in embryonic cells. We have demonstrated that the expression profile of brain-enriched miRNA-7, which is processed from a ubiquitous pre-mRNA transcript coding for hnRNP K protein, is achieved by inhibition of its biogenesis in non-brain cells. By identifying MSI2 and HuR proteins as inhibitors of miRNA-7 maturation in non-brain cells we provided the first insight into the regulation of brain-enriched miRNA processing by defined tissue-specific factors. Furthermore, we showed that brain-specific miRNA-9 is regulated transcriptionally and post-transcriptionally during neuronal differentiation. We revealed that Lin28a, an RNA-binding protein progressively switched off during differentiation, inhibits the processing of brain-specific miRNA-9 by inducing the degradation of its precursor transcript during early stages of neuronal differentiation. Our findings have far reaching consequences for our understanding of how RNA-binding proteins commit to a specific molecular function and how, through targeting miRNA biogenesis pathway, they contribute to control of gene expression mammalian cells.