The p53 tumor suppressor gene plays a key role in prevention of tumor formation through transcriptional dependent and independent mechanisms. Transcriptional-dependent mechanisms are mainly mediated by p53 regulation of downstream targets, leading to growth arrest and apoptosis. Mutational inactivation of the p53 gene is detected in more than 50% of human cancers. Mutation of p53 renders cancer cells more resistant to current cancer therapies due to lack of p53-mediated apoptosis. Extensive studies have been conducted to identify small molecules that manipulate p53, including restoration of mutant p53 conformation to wild-type, disruption of murine double minute-2 (Mdm2)-p53 binding to increase p53 level and inhibition of Mdm2 E3 ubiquitin ligase activity to prevent p53 degradation. Another approach was to identify and validate “drugable” target(s) in p53 signaling pathways that modulate p53-induced apoptosis. We profiled a p53 temperature-sensitive lung cancer cell model with the Affymetrix human HG-U133 GeneChip, covering the entire human transcriptome. We identified thousands of unique genes that were either induced or repressed in response to p53-induced apoptosis. A follow-up study characterized a p53-repressed gene, SAK, a polo-like kinase (PLK) family member, as an appealing cancer drug target. Snk/Plk-akin kinase (SAK) silencing via small interfering RNA (siRNA) induced apoptosis, whereas SAK overexpression attenuated p53-induced apoptosis. Thus, SAK repression by p53 contributes to p53-induced apoptosis. Future work is directed at determining the normal cell response to SAK silencing. If a therapeutic window is obtained, a SAK inhibitor identified from high throughput screening (HTS) could serve as a lead compound for development of a novel class of apoptosis-inducing anticancer drugs. © 2006 Wiley-Liss, Inc.