The study by Doench and Sharp investigates the specificity of microRNA (miRNA) target selection in translational repression. They find that the ability of an miRNA to repress a target mRNA is largely determined by the free energy of binding of the first eight nucleotides in the 5' region of the miRNA. However, G:U wobble base-pairing in this region interferes with activity beyond what is predicted based on thermodynamic stability. The level of repression achieved depends on both the amount of mRNA and the amount of available miRNA complexes. The authors also demonstrate that an mRNA can be simultaneously repressed by more than one miRNA species, and that the presence of multiple miRNAs can increase repression. They conclude that predicted miRNA:mRNA interactions must be considered in the context of other potential interactions and cellular conditions.The study by Doench and Sharp investigates the specificity of microRNA (miRNA) target selection in translational repression. They find that the ability of an miRNA to repress a target mRNA is largely determined by the free energy of binding of the first eight nucleotides in the 5' region of the miRNA. However, G:U wobble base-pairing in this region interferes with activity beyond what is predicted based on thermodynamic stability. The level of repression achieved depends on both the amount of mRNA and the amount of available miRNA complexes. The authors also demonstrate that an mRNA can be simultaneously repressed by more than one miRNA species, and that the presence of multiple miRNAs can increase repression. They conclude that predicted miRNA:mRNA interactions must be considered in the context of other potential interactions and cellular conditions.