Dietary selenium intake is regarded as an important factor in determining optimal health and susceptibility to disease. Therefore, it is critical to understand the interaction between selenium intake and molecular events at the genetic and cellular level. This article addresses two facets of this interaction. The first facet is how genomics is contributing to understanding the molecular mechanisms by which selenium affects cell function through selenoproteins and downstream targets of Se supply in other metabolic pathways. The contribution of transgenic animals in this field is emphasized, and the more recent studies using transcriptomics are discussed. The second facet is the extent to which single nucleotide polymorphisms (SNPs) in genes encoding selenoproteins and components of the selenoprotein synthetic machinery affect individual dietary requirements for optimal health. The state of knowledge of known functional SNPs in selenoprotein genes is presented, and a strategy for future studies is discussed.