Exceptional longevity represents an extreme phenotype. Current centenarians are survivors of a cohort who display delayed onset of age-related diseases and/or resistance to otherwise lethal illnesses occurring earlier in life. Characteristics of aging are heterogeneous, even among long-lived individuals. Associations between specific clinical or genetic biomarkers exist, but there is unlikely to be a single biomarker predictive of long life. Careful observations in the oldest old offer some empirical strategies that favor increased health span and life span, with implications for compression of disability, identification and implementation of lifestyle behaviors that promote independence, identification and measurement of more reliable markers associated with longevity, better guidance for appropriate health screenings, and promotion of anticipatory health discussions in the setting of more accurate prognostication. Comprehensive PubMed literature searches were performed, with an unbiased focus on mechanisms of longevity. Overall, the aggregate literature supports that the basis for exceptional longevity is multifactorial and involves disparate combinations of genes, environment, resiliency, and chance, all of which are influenced by culture and geography.