The CDKN2A gene is a tumor suppressor that encodes the CDK4/6 inhibitor p16(ink4a). Loss of this tumor suppressor contributes to the bypass of critical senescent signals and is associated with progression to malignant disease. However, the high-level expression of p16(ink4a) in tumors is associated with aggressive subtypes of disease, and in certain clinical settings elevated p16(ink4a) expression is an important determinant for disease prognosis and therapeutic response. These seemingly contradictory facets of p16(ink4a) expression have lead to confusion related to the meaning of this tumor suppression in tumor pathobiology. As reviewed here, the alternative expression of p16(ink4a) represents an ideal marker for considering RB-pathway function, tumor heterogeneity, and novel means for directing therapy.