Protein Kinase C (PKC) isozymes have been implicated in the control of such diverse cellular functions as proliferation, differentiation, polarity and survival. Since the discovery that PKCs are cellular receptors for the tumor promoting phorbol esters, they have been implicated in various aspects of cancer. Distinct changes in the pattern of PKC expression and activity have been associated with the transformed phenotype of cancerous cells, and disruption of the activity/expression of multiple PKC isozymes can affect the transformed phenotype. However, direct genetic evidence that any PKC isozyme is a human oncogene had been lacking. We recently demonstrated that the atypical PKC isozyme PKCι is an oncogene in non-small cell lung cancer (NSCLC) (1). PKCι expression is elevated in the vast majority of NSCLC cell lines and primary tumors and PKCι expression correlates with poor clinical outcome in NSCLC patients. Interestingly however, PKCι expression is elevated in both early and late stage disease. Therefore, PKCι expression profiling holds particular promise as a prognostic marker to identify NSCLC patients with early stage disease who are at high risk for relapse. PKCι expression in NSCLC tumors is driven by tumor-specific amplification of the PKCι gene in ~30% of NSCLC cases. PKCι gene amplification drives PKCι expression in these tumors. Functionally, genetic disruption of PKCι expression inhibits multiple aspects of the transformed phenotype including transformed growth in soft agar, invasion through Matrigel, and growth of subcutaneous tumors in nude mice (2). Genetic dissection of the oncogenic PKCι signaling pathway demonstrate that PKCι drives transformed growth by activating a PKCι→ Rac1→ Pak→Mek1,2→Erk 1,2 signaling pathway that is required for transformed growth (2). The transforming activity of PKCι requires the N-terminal Phox-Bem 1 (PB1) domain of PKCι which serves to couple PKCι to downstream effectors via adaptor molecules. We have designed and implemented a high throughput drug screen to identify compounds that can disrupt PB1-PB1 domain interactions between PKCi and the adaptor molecule Par6 (3). Our screen identified the gold compound aurothiomalate (ATM) as a potent and specific inhibitor of the PB1 interactions between PKCι and Par6 that exhibits potent anti-tumor activity against NSCLC both in vitro and in vivo. Structural analysis, site-directed mutagenesis and modeling indicate that ATM specifically targets the PB1 domain of PKCι to mediate its anti-tumor activity (4). ATM is currently in phase I clinical trials for the treatment of NSCLC. Molecular aspects of oncogenic PKCι signaling will be discussed with a particular emphasis on their implications for diagnosis of cancer, use as prognostic markers, and potential as novel therapeutic targets.