An article in the current Advance Online Publication section of Nature Genetics reports the results of a large-scale RNA interference (RNAi) screen for genes that, when down-regulated, produce enhanced longevity in the nematode Caenorhabditis elegans. The down-regulation of a large number of genes related to energy metabolism and mitochondrial function yielded animals with increased life-spans, albeit with some additional deleterious phenotypes in some cases. In this Perspective, I discuss the implications of these results and make a plea for a more integrated approach in assessing the role of mitochondrial function, single gene mutations, and longevity.