Technical Abstract: Selenium was discovered by Berzelius in 1817, and the essentiality of Se was demonstrated that trace amounts of Se protected against liver necrosis in vitamin E deficient rats in the mid-1950s. The benefits of Se are many including protection against cancer, heart diseases, muscle disorders, immunity and age-related diseases. The health-promoting properties of Se are due to vital functions of selenoproteins, and Se compounds have been considered to act as Se donors for selenoprotein biosynthesis which is required for normal physiology. However, chemoprevention, in most cases, was obtained with small Se-metabolite molecules such as selenide and methylselenol through supranutritional intake. Investigations into the protective role of Se had been undertaken for many years both in animal and case-control, but not all nutritional intervention studies show that high Se intakes effectively reduce cancer risk. This is because there is a relatively narrow margin between Se intakes that result in deficiency or toxicity. Various underlying mechanisms have been presented which, however, may also differ depending on the chemical form of Se and the time point of intervention. The regulation of cell cycle and apoptosis is the most fundamental biological process related to Se’s health-promoting properties. It has been well recognized that Se plays a critical role in cell proliferation but the mechanism remains elusive. In humans and animals, cell proliferation must be regulated to maintain tissue homeostasis. The eukaryotic cell cycle is divided into four major phases as follows: the G1 phase before DNA replication, the periods of DNA synthesis (S phase), the G2 phase before cell division and cell division (M phase). The cell cycle is a conserved mechanism by which eukaryotic cells replicate themselves, and apoptosis is also a highly conserved mechanism by which eukaryotic cells commit suicide. Apoptosis, a programmed cell death, enables an organism to eliminate unwanted and defective cells during normal development, turnover and pathological conditions. There are several putative mechanisms by which Se modulates cell cycle and apoptosis, and these mechanistic aspects may reveal the relationship between Se and health outcomes, including cancer and inflammatory disorders.