MicroRNAs (miRNAs) control gene expression by regulating mRNA stability and translation. Using cell-free in vitro systems, several labs have recently reported insights into the molecular mechanisms underlying miRNA-guided translational repression (Kiriakidou et al., 2007; Mathonnet et al., 2007; Thermann and Hentze, 2007; Wakiyama et al., 2007). These new findings indicate that miRNAs inhibit translation at early steps of initiation.