The RNA exosome is a major ribonuclease complex that participates in the surveillance and decay of virtually all classes of RNAs in both the nucleus and cytoplasm of eukaryotic cells, as well as in the processing of selected nuclear RNAs. The RNase activity of the exosome is embedded in a 10-subunit core complex and is regulated by specific nuclear and cytoplasmic cofactors. Central to these cofactors are the nuclear RNA helicase Mtr4 and the cytoplasmic helicase Ski2, which are thought to recognize and remodel substrates and channel them to the core complex for degradation. Structural and biochemical studies over the past years have revealed how the yeast Mtr4 helicase recognizes and processes a complex ribonucleoprotein particle such as the precursor of the 60S ribosomal subunit and have also shown that the Mtr4-channeling mechanism is conserved in the human nuclear exosome complex. As an additional layer of complexity, the exosome helicases are themselves part of protein complexes. While there are different Mtr4-complexes in the nucleus, in the cytoplasm there appears to be a single Ski2-containg complex (Ski) that interacts with 80S ribosomes. How association of the Mtr4 and Ski2 helicases in protein complexes impacts on their function is largely unknown. The talk will delve into the layers of regulatory mechanisms that are beginning to emerge.