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Cotranslational targeting to the ER is pervasive and is principally determined by the location of the hydrophobic targeting sequence within the protein, rather than the mechanism of targeting or translocation. The position of this hydrophobic domain within the open reading frame determines the duration of time a targeted ribosome nascent-chain complex (RNC) can associate with the ER. Our data suggest a role for polysomes in retaining mRNAs at the ER, allowing for efficient targeting of RNCs for translocation. Position-specific analyses revealed that distinct translocon complexes engage nascent chains at different points during synthesis. Most proteins engage the ER immediately after or even before the signal sequence or signal anchor emerges from the ribosome. These nascent chains typically undergo a conformational rearrangement within the translocon, the proteinaceous tunnel through which nascent proteins cross the ER membrane. This rearrangement results in a “looped” conformation of the nascent chains, with their N termini facing the cytosol. This conformation is required for signal sequence processing. However, we discovered a class of Sec66-dependent proteins that engage only when they are long enough to adopt the looped conformation. Finally, we monitored the fate of ER-associated ribosomes after translation termination using pulsed-labeling experiments. These data demonstrated that ER-associated ribosomes readily exchanged into the cytosol after at most a few rounds of translation at the ER.