The increasing longevity of the population, one of the most important issues throughout the planet, is a very complex phenomenon (trait), likely resulting from a variety of environmental determinants interacting with and modulated by genetic mechanisms, mostly devoted to maintenance and repair. In fact, the genes involved in longevity impact upon basic processes such as inflammation, glucose and energy utilization, and oxidative stress. Based on the free radical theory of aging, in the past few years we have focused our attention on an enzyme that protects lipids from peroxidative damage—paraoxonase 1 (PON1). PON1 has been widely investigated, especially for its involvement in atherosclerosis and age-related diseases. In this review, we summarize data on the role played by PON1 on aging and its possible involvement in human longevity, focusing on the relationship between genetic polymorphisms and enzyme activity and its capability to counteract oxidative stress.