In both esophageal and NSCLC, the TNM stage at diagnosis remains the most important determinant of survival. Significant research to investigate the biology of NSCLC and esophageal carcinoma is ongoing, and the roles of proto-oncogenes, tumor suppressor genes, angiogenic factors, extracellular matrix proteases, and adhesion molecules are being elucidated. While evidence is accumulating that various markers are involved in NSCLC and esophageal tumor virulence, the current studies are compromised by small sample sizes, heterogeneous populations, and variations in techniques. Large prospective studies with homogenous groups designed to evaluate the role of these various markers should clarify their potential involvement in NSCLC and esophageal cancer. Identification of occult micrometastases in lymph nodes and bone marrow using immunohistochemical techniques and rt-PCR is intriguing. These techniques are promising as a method to more accurately stage patients, and therefore to predict outcomes and to determine therapies. Perhaps the most promising area of research is the development of novel drugs whose mechanism of action targets the pathways of various molecular markers. Molecular biologic substaging offers an opportunity to individualize a chemotherapeutic regimen based on the molecular profile of the tumor, thus providing the potential for improved outcomes with less morbidity in patients with both NSCLC and esophageal cancer.