Lung cancer is the most prevalent malignant tumor in the world. Metastasis of the disease causes death in lung cancer patients. Recent study has shown that multiple cascades of gene defects occur in lung cancer. In this report, we established a novel H1299/EGFP tumor model to determine whether H1299 transfected with the enhanced green fluorescent protein (EGFP) gene in vitro and xenotransplanted into SCID mouse lung would permit the detection of lung cancer micrometastasis in vivo. We demonstrated that EGFP-transduced H1299 cells maintained stable high-level EGFP expressions during their growth in vivo. EGFP fluorescence clearly demarcated the primary seeding place and readily allowed for the visualization of distant micrometastasis and local invasion at the single-cell level. Small metastatic and locally invasive foci, including those immediately adjacent to the tumor's leading invasive edge, were almost undetectable by routine hematoxylin and eosin staining and immunohistochemistry. The GFP tagged lung cancer model is superior for the detection and study of physiologically relevant patterns of lung cancer invasion and metastasis in vivo.