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.