The ARF tumor suppressor is a common target in human cancer, second only to p53 in its frequency of disruption. ARF is widely regarded as a major upstream activator of p53 in response to hyperproliferative signals. However, the emergence of a second, p53-independent ARF pathway has changed the way we think about ARF tumor surveillance. Specifically, animal models have provided genetic evidence of an alternative ARF pathway. Mice lacking ARF and p53 exhibit a more profound tumor spectrum when compared to single-null ARF or p53 littermates and eye defects observed in ARF or ARF/p53-null animals are not seen in p53-null mice. Recent experiments have further demonstrated that ARF can induce cell growth arrest in the presence of mutant p53, or in the absence of p53 and Mdm2 altogether. In search of p53-independent ARF targets, we have isolated a novel ARF binding protein, nucleophosmin (NPM), a key regulator of centrosome duplication. An intriguing aspect of this finding is the notion that ARF, through its interaction with NPM, may function as a master brake of centrosome duplication, and that the Mdm2 oncogene dictates ARF's tumor suppressive capability. Identifying the mechanisms behind ARF's role as a tumor suppressor is of utmost significance in our view of the "big picture".