Once in the cytoplasm, any mRNA will eventually undergo deadenylation in which the poly(A) tail is removed one adenine at a time and this process is considered to be the rate-limiting step of mRNA decay. Two protein complexes are responsible for mRNA deadenylation in eukaryotes: PAN2-PAN3 and CCR4-NOT. Initially, it was proposed that deadenylation is a stepwise process where PAN2-PAN3 is responsible for deadenylating longer poly(A) tails and CCR4-NOT then takes over. However, more recent findings have challenged this hypothesis and shown that CCR4-NOT subunits can displace PABP. Furthermore, sequence specific RNAbinding proteins can recruit CCR4-NOT (Fig. ) to their bound transcripts and fully bypass PAN2-PAN3 catalyzed deadenylation. Although both exonuclease complexes are important, only the depletion of the CCR4-NOT complex from mammalian cells improves overall mRNA half-life while depletion of PAN2-PAN3 seems to have no effect. Therefore, targeting the CCR4-NOT complex by chemical modulators can potentially be used in regulating poly(A) tail length and therefore mRNA half-life and stability.