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Summary: Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5′ leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA. : Rocaglates are a diverse family of small molecules that inhibit eIF4A. Chu et al. undertake a comparative analysis of the bioactivity of >200 rocaglates and uncover nuances in their mechanisms of action. Rocaglates interfere with eIF4F release from the cap and exert a bystander effect to inhibit translation. Keywords: rocaglates, eIF4A, eIF4F, translation initiation, interfacial inhibitor