In eukaryotes, a pre-messenger RNA (pre-mRNA) must undergo several processing reactions before it is exported to the cytoplasm for translation. One of these reactions, endonucleolytic 3' cleavage at the polyadenylation site, prepares the pre-mRNA for addition of the poly(A) tail and defines the 3' untranslated region (UTR), which typically contains important gene expression regulatory sequences. While the protein factors responsible for the endonucleolytic cleavage have been largely identified, the means by which their action is limited to the 3' end of the transcription unit and coordinated with other co-transcriptional events remains unclear. In this review, we summarize and review recent findings revealing that the mammalian 3' cleavage factors undergo extensive post-translational modification. These modifications include: arginine methylation, lysine sumoylation, lysine acetylation, and the phosphorylation of serine, threonine and tyrosine residues. Every cleavage factor, though not every subunit, is affected. Human Fip1 and the 59 kDa subunit of cleavage factor I emerge as the most frequently modified core cleavage factor subunits. We outline and compare the various proteomic methods that have uncovered these modifications, and review emerging hypotheses concerning their function. The roles of these covalent but reversible modifications in other systems suggest that 3' end formation in mammals relies upon post-translational modification for proper function and regulation.