What does it take to live to be 100 and …. enjoy it? How do we stay healthy and active until a very old age? To a significant extent, it depends on our behavior, life style and the societies we live in. But environmental factors are just one side of the story; our genetic predisposition plays an important role as well. During the first 85 years of life, genes have only a relatively small effect on our ability to survive. But the older we get, the more they matter. And once we reach the 90s, the genetic influence is quite substantial (> 30%). Many genes are likely to contribute to the longevity phenotype, though each of them seems to have only a modest effect. Surprisingly, many long-lived individuals (LLI), i.e. nonagenarians and centenarians, are in robust health and show a favorable course of the ageing process, with the absence or delayed onset of typical age-related diseases. LLI are therefore considered excellent models for healthy ageing and offer us – The Research Group for Healthy Ageing – and other scientists worldwide the key to identifying the genes and molecular pathways that positively modulate human life and health span. Preliminary research suggests that the genomes of most LLI are enriched with longevity-promoting variants (as seen for instance in the gene FOXO3A) that may offset some of the deleterious effects of disease genes and ageing processes. The longevity variants and their underlying buffering mechanisms could provide a basis for intervention strategies that are aimed at the alleviation and/or prevention of age-related and other diseases.