Activation of cell-surface receptors by insulin triggers a signalling cascade in the cell that is mediated by the enzyme PI3K and subsequently by FOXO transcription factors. Kalaany and Sabatini find that dietary restriction reduces the activity of this pathway in some tumour cells, thereby enhancing cell death and reducing tumour size. However, tumours in which this pathway is constitutively active — owing to mutations in PI3K or in the PTEN enzyme, which normally counteracts PI3K — are resistant to the beneficial effects of dietary restriction.