MicroRNAs (miRNAs) are a class of small RNAs with diverse regulatory roles. The discovery of miRNAs and closely related small-interfering RNAs (siRNAs) is a watershed moment in biology that has changed traditional views of genetic regulation and has placed small RNAs alongside transcription factors as critical regulators of gene expression. But what regulates these regulators? Recent studies indicate that miRNA biogenesis can be posttranscriptionally regulated by trans-acting factors. The Lin28/let-7 partnership is the best characterized example of the relationship between an miRNA and its posttranscriptional regulator and may shed light on the posttranscriptional regulation of other miRNAs. Here, we highlight recent advances in our understanding of the posttranscriptional regulation of the let-7 miRNA by the conserved RNA-binding protein Lin28 and show how this impacts our understanding of pluripotency, development, and cancer.