Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide. Despite progress in therapeutic and surgical treatments, its survival period at 5 years is the lowest among major cancers, and remains unchanged in the last two decades. The growing epidemiological relevance of oral cancer emphasizes the need to better understand the molecular mechanisms underlying this disease and identify predictive tumor markers. To this end, we have used DDRT-PCR to profile the oral tumor transcriptome and identify differentially regulated genes that may function as potential therapeutic targets. Our DDRT-PCR analysis identified 51 differentially expressed fragments of which 25 were revalidated by reverse Northern analysis. Northern blot analysis further corroborated these findings for a few genes. In order to ascertain the utility of some of the identified genes as molecular markers, semi-quantitative RT-PCR analysis was carried out in a panel of matched oral normal and tumor samples, that confirmed GLTP, PCNA, RBM28, C17orf75 and DIAPH1 as significantly unregulated, whereas TNKS2, PAM and TUBB2C showed significant down regulation in tumor samples. Taken together, our DDRT-PCR analysis has revealed several genes, belonging to diverse cellular pathways that have been associated with oral cancer for the first time. Thus, these genes could be investigated as biomarkers and therapeutic targets for OSCC.