Objectives: 1) Identify genes deregulated through altered DNA methylation in oral cancer. 2) Gain a better understanding of pathways involved in OSCC progression.Methods: Multiple biopsies were obtained from an oral cancer (OC) field exhibiting hyperplasia, dysplasia, and carcinoma in situ (CIS)/squamous cell carcinoma (SCC) from ten patients. DNA and RNA from microdissected tissue samples were extracted. Methylation levels were obtained using the Illumina Infinium HumanMethylation27K microarray, and gene expression levels were assessed using the Agilent Human Gene Expression 4x44k microarray. Significant genes were identified using a Wilcoxon signed rank test. Data from both platforms were integrated and candidate genes identified. Results:We identify numerous genes that exhibit both aberrant methylation and matched altered gene expression. In oral dysplasias we identify PEG10 and SOX17 as being frequently deregulated. These genes have roles in the TGFbeta and WNT signal transduction pathways, respectively, and crosstalk between these two pathways has been observed previously in tumorigenesis. In the CIS/SCC biopsies, we observe 67 genes hypermethylated and 113 hypomethylated in at least 30% of cases with matched altered gene expression.Conclusions: This is the first report integrating profiles of DNA methylation and gene expression data for different histological stages of OC. Given the frequency of methylation and expression correlating with one another, we demonstrate that methylation is one of the critical mechanisms in OC progression.