BTG2 is a prototype member of the BTG/Tob family of antiproliferative proteins, originally identified as a primary response gene induced by growth factors and tumour promoters. Its expression has been linked to diverse cellular processes such as cell-cycle progression, differentiation or apoptosis. BTG2 has also been shown to interact with the Pop2/Caf1 deadenylase. Here, we demonstrate that BTG2 is a general activator of mRNA decay, thereby contributing to gene expression control. Detailed characterizations of BTG2 show that it enhances deadenylation of all transcripts tested. Our results demonstrate that Caf1 nuclease activity is required for efficient deadenylation in mammalian cells and that the deadenylase activities of both Caf1 and its Ccr4 partner are required for Btg2-induced poly(A) degradation. General activation of deadenylation may represent a new mode of global regulation of gene expression, which could be important to allow rapid resetting of protein production during development or after specific stresses. This may constitute a common function for BTG/Tob family members.