This Commentary discusses new data from the laboratory of Matthias Hentze (Schell et al., in this issue) that begins to dissect the RNA–protein and protein–protein interactions important for the process of nonsense-mediated decay (NMD). Schell and co-workers have developed a novel tool for analysis of such interactions in vivo. Using a proteomics approach, they have identified two different protein–RNA complexes that contain human Upf (up-frameshift) proteins central to the NMD process. Intriguingly, they identified a poly[A]-binding protein associated with these complexes.