Caloric restriction is the only known non-genetic intervention that robustly extends lifespan in mammals. This regimen also attenuates the incidence and progression of many age-dependent pathologies. Understanding the genetic mechanisms that underlie dietary-restriction-induced longevity would therefore have profound implications for future medical treatments aimed at tackling conditions that are associated with the ageing process. Until recently, however, almost nothing was known about these mechanisms in metazoans. Recent advances in our understanding of the genetic bases of energy sensing and lifespan control in yeast, invertebrates and mammals have begun to solve this puzzle. Evidence is mounting that the brain has a crucial role in sensing dietary restriction and promoting longevity in metazoans.