Besides nascent and fully synthesized precursor polypeptides, mRNAs are targeted to the human endoplasmic reticulum (ER). In contrast to precursor targeting, however, little is known about mRNA targeting. To gain novel insights into the latter process, we combined siRNA-mediated depletion of putative ER-membrane resident mRNA- receptors in HeLa cells with label-free quantitative proteomics and differential expression analysis.