By binding cyclin D1, functional p16^INK4a contributes to the maintenance of the pRb in its unphosphorylated or hypophosphorylated state, which in turn inhibits cell cycle progression. The expression of p16^INK4a is up-regulated by Ets and down-regulated by Bmi-1. Inactivation of p16^INK4a by deletion, mutation, methylation and aberrant splicing can lead to unlimited cell cycle progression and tumorization. Reasonably, p16^INK4a is now selected to treat some kind of tumors, but research in this field remains a long way to go.