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T he genetic basis for the attenuation of polio vaccines has been known since the 1980s. Changes in the internal ribosome entry site, within the 5′ noncoding region of genomic RNAs, were presumed to reduce translation in certain target organs, leading to the conclusion that attenuation is mediated at the level of translation. A report in this issue of the JCI reveals that poliovirus tropism is, in part, determined after internal ribosome entry.