Since their discovery almost two decades ago, microRNAs (miRNAs) have been shown to function by post-transcriptionally regulating protein accumulation. Understanding how miRNAs silence targeted mRNAs has been the focus of intensive research. Multiple models have been proposed, with few mechanistic details having been worked out. However, the past few years have witnessed a quantum leap forward in our understanding of the molecular mechanics of miRNA-mediated gene silencing. In this review we describe recent discoveries, with an emphasis on how miRISC post-transcriptionally controls gene expression by inhibiting translation and/or initiating mRNA decay, and how trans-acting factors control miRNA action.