The delta isoform of Protein Kinase C (PKC-δ) is a potential tumor suppressor gene for human squamous cell carcinomas (SCCs). The objective of this study is to investigate the mechanism of PKC-δ loss in human SCCs. We used Laser Capture Microdissection to isolate cells for nucleic acid analysis from normal epidermises and human SCCs. Using this approach, we found that PKC-δ is lost at the mRNA level in human SCCs, and that the PKC-δ gene is rarely deleted suggesting that the mechanism of down-regulation of PKC-δ in SCCs is at the level of gene transcription. Further investigation identified a novel Ras→PI3K→Fyn→NF-κB signaling pathway necessary and suffcicient for PKC-δ repression in human keratinocytes. Our results have implications for the development of therapeutic strategies abrogating this signaling pathway to trigger the re-expression of pro-apoptotic PKC-δ to induce apoptosis in SCCs.