For many chronic diseases, the influence of genetics is complex and phenotypes do not conform to simple Mendelian patterns of inheritance. Discussed here are two types of genetic influences on healthy aging. The first involves variation in the gene sequence itself and how this may influence disease susceptibility, progression, and severity, interacting with other recognized risk factors. The second involves epigenetic regulatory mechanisms that may potentially provide insight into how environmental influences affect the expressed genome, thus improving our understanding of the genetic mechanisms underlying multifactorial diseases. The interleukin-1 family of cytokines can be used to illustrate how genetic sequence variation may affect such diseases. This cytokine family plays a key role in mediating inflammation, which is now understood to be a central component of a growing number of chronic diseases. Recent work has revealed many sequence variations in the regulatory DNA of genes encoding important members of the interleukin-1 family, and these variations are associated with differential effects on the inflammatory response. The interactions of environmental factors with both DNA sequence variations and epigenetic modifications are likely to determine the phenotypes of multifactorial diseases of aging as well as the phenotype of healthy aging.