Characterization of regulatory mechanisms affecting microRNA (miRNA) expression and activity is providing novel clues for the identification of genes and complex regulatory circuits that determine cell and tissue specificity. Here, we review the molecular events leading to miRNA biogenesis and activity, focusing above all on endogenous and epigenetic transcriptional networks involving miRNA in early development, cellular lineage specification/differentiation of nervous, skeletal and cardiac muscle tissues and in haematopoiesis, as the de-regulation of such networks may be relevant to disease pathogenesis.