Reversal of cancer cachexia and muscle wasting by blocking the activin type II receptor (ActRIIB) prolongs survival, even in the setting of continued tumour growth. ActRIIB mediates signalling of a subset of TGF-β proteins, including myostatin, activin A, activin B and GDF-11. Of these proteins, we demonstrate that the activin isoforms are, by far, the most potent negative regulators of muscle mass. Importantly, elevating circulating activin A alone, using a recombinant viral vector-based system, is sufficient to replicate the muscle and fat loss observed in cancer cachexia. Mechanistically, activin A reduces muscle mass and functional capacity by hijacking the myostatin signalling pathway, leading to a decrease in Akt/mTOR-mediated protein synthesis and an increase intranscription of atrophy-related ubiquitin ligases. Activin A also induces a sustained fibrotic response within muscle. Critically, our data demonstrate that the muscle wasting and fibrosis that ensues in skeletal muscle in response to activin A is fully reversible, highlighting the potential therapeutic benefits that may be gained from targeting activin A in muscle wasting diseases, such as cancer cachexia. To this end, we have recently developed the first activin-specific antagonists and shown that these reagents can protect muscles from activin-induced wasting.