Located on chromosome 9p21.3, p16INK4a seems lost amongst a cluster of neighboring tumor suppressor genes. While best known for inhibiting cyclin dependent kinase (CDK) activity, p16INK4a is not a one trick pony. Long term p16INK4a expression pushes cells to enter senescence, an irreversible cell cycle arrest that prevents the growth of would-be cancer cells, but also contributes to aging. Loss of p16INK4a is one of the most frequent events in human tumors and allows pre-cancerous lesions to bypass senescence. Therefore, precise regulation of p16INK4a is essential to tissue homeostasis, maintaining a tight balance between tumor suppression and aging. Here, we outline the pathways required for proper p16INK4a regulation and highlight the critical functions of p16INK4a in cancer, aging and human physiology that make this gene special.