The DNA-dependent protein kinase (DNA-PK) has a vital role in DNA double strand break repair and in mediating V(D)J recombination events. Over the years a body of data has implicated DNA-PK playing a significant role in mediating a p53-dependent apoptotic response under a range of cellular conditions including exposure to ionizing radiation (IR), environmental carcinogens, and chemotherapeutic agents or in cells that have critically shortened telomeres. These findings raise the hypothesis that DNA-PK acts as both a sensor and transmitter of DNA damage signals that directly impact cell fate. These many overlapping roles are discussed and considered in this review article.