Cancer of the esophagus is of two main types, each with distinct etiological and pathological characteristics. Esophageal squamous cell carcinoma (ESCC) is predominant type of esophageal cancers worldwide comprising almost 95% of cases. While ESCC is prevalent in the developing world, esophageal adenocarcinoma is commonly seen in the developed country, usually in association with Barrett's esophagus. In spite of its higher prevalence, ESCC has not been studied as intensively as esophageal adenocarcinoma. ESCC and esophageal adenocarcinoma are common cancers worldwide with poor survival rate among patients mainly because both of these cancers lack early biomarkers of identification. Molecular mechanisms contributing to initiation and progression of esophageal squamous cell carcinoma are still poorly understood. Development of DNA microarray technology allows high-throughput identification of gene expression profiles in cancers. In order to identify molecules as candidates for early diagnosis and/or as therapeutic targets, we analyzed the mRNA expression profiles of 20 cases of ESCC using whole genome DNA microarrays. A total of 2,235 genes were differentially regulated in the tumors as compared to the corresponding adjacent normal epithelium of which 881 were significantly upregulated. We validated two molecules that were not previously reported to be overexpressed in ESCC, oral cancer overexpressed 2 (ORAOV2) and fibroblast activation protein (FAP), by immunohistochemical labeling of tissue microarrays and archival tissue sections and found that they were overexpressed in 98% (116/118) and 68% (79/116) of cases, respectively. By gene enrichment analysis, we identified significant downregulation of several genes in the arachidonic acid metabolic pathway. Overall, using this approach we have identified a number of promising novel candidates that can be validated further for their potential to serve as biomarkers for ESCC.