The Atlas human cDNA expression array was used to evaluate gene expression profile changes in the genesis of human lung adenocarcinomas and squamous cell carcinomas. Gene expression changes between adenocarcinomas and squamous cell carcinomas were also analyzed. Of the 588 gene targets, 262 genes were expressed in these tissues and, of these, 45 genes were differentially expressed by at least two-fold in tumor tissues compared to corresponding normal tissues. Semiquantitative reverse-transcriptase polymerase chain reaction was used to confirm gene expression changes. Only those genes that reflected changes in >50% of the analyzed tissues were included in the final analysis. Ultimately, 26 genes were evaluated with 14 genes overexpressed and 12 genes underexpressed compared to matching normal lung tissues. Although similar expression changes were detected in adenocarcinomas and squamous cell carcinomas for most of the genes analyzed, some subtype-specific differences were also found. Genes encoding cell cycle regulators, intracellular signal transducers, cell receptor and adhesion molecules, growth factors, oncogenes, and apoptotic effectors were differentially expressed in this study. These gene expression changes may directly contribute to the initiation or progression of human lung cancer or may be secondary effects of the tumorigenesis process. Regardless, many of these differences may be useful in the diagnosis and/or treatment of this deadly disease.