This chapter covers the complete life cycle of microRNAs, from start to finish. Beginning with their location in the genome, how they are transcribed and some of the factors that switch microRNAs on and off, it moves next to the biochemical steps involved in the step-wise processing of the precursor RNA by the enzymes Drosha and Dicer, before the microRNA is eventually loaded into a pocket in the Argonaute protein ready to carry out gene silencing. For some steps, a deeper look is taken into the atomic structures of these biological nanomachines and how they pivot and adjust to join together proteins and RNA as they perform their functions. This includes the remarkable search strategy by which the gene silencing complex containing a microRNA probes for binding sites on mRNA targets. Finally comes the molecular decision-making behind how much protein is reduced and by what mechanism. The when and how a microRNA knows its work is done and what finally extinguishes its effects. Again, the chapter conveys the intense competition among scientists vying to answer the next question and the one after that, which was a potent accelerant for discovery.