This review focuses on the role of the INK4a/ARF locus in human cancer. Several excellent related reviews have recently been published (1 –5 ). Rather than presenting protocols, this review will describe the current state of the field. However, in keeping with the goals of these monographs, emphasis will be placed on the methods used to generate our current understanding. In particular, the methodologic challenges posed by the unusually dense structure of the locus will be highlighted.