This chapter reviews the present state of knowledge on the activity of enzymes that function with the RNA exosome in the nucleus. In this compartment, the exosome interacts physically and functionally with the exoribonuclease Rrp6 and several cofactors, most prominently Rrp47 and the TRAMP complex. These interactions decide the fate of RNA precursors from transcription through the formation of mature ribonucleoprotein particles (RNPs) and the export of the RNPs to the cytoplasm. The nuclear exosome catalyzes the formation of the mature 3′ ends of many of these RNAs, but in other cases degrades the RNAs to mononucleotides. Cofactors such as Mpp6, TRAMP and the Nrd1/Nab3 complex play important roles in determining the outcome of the interaction of RNPs with the nuclear exosome. The details that govern the specificity of these decisions remain a rich source for future investigation.