This chapter presents how scientists currently use the increasing number of individuals who live to an age above 90 years (i.e. long-lived individuals) to investigate biological determinants of longevity. It will provide an overview of the most extensive studies of exceptionally long-lived individuals and long-living families that have been established since the early 1970s. The focus of the chapter will be on the metabolic phenotypes and the genetic determinants that characterize them. It will discuss the delayed occurrence of age-related disease in long-lived individuals and their offspring as well as their favourable immune-metabolic profile, that is, improved glycaemic control, lipid and thyroid metabolism and immunity. Moreover, it will provide an overview of studies focused on unravelling the genetic component of longevity, which is assumed to be partly responsible for the observed immune-metabolic profile. The findings from these studies indicate that longevity is most likely determined by many different rare protective genetic variants that still need to be identified, for example using whole genome/exome sequencing approaches. Last, but not least, the chapter will discuss some of the implications of the presented findings for medical research on ageing and age-related diseases.