Five families of activated protooncogenes, ras, raf, jun, erbB-2 (neu) and myc have so far been associated with human bronchogenic carcinoma. Human bronchial epithelial cells in vitro are being used to investigate the functional role of these specific oncogenes and growth regulatory genes in carcinogenesis and tumor progression. When transferred into normal human bronchial epithelial cells, the vHa-ras oncogene initiates a cascade of events leading to their decreased responsiveness to inducers of squamous differentiation, aneuploidy, and, less frequently, """"""""immortality"""""""" and tumorigenicity with metastasis in athymic nude mice. Transfection of the SV40 T antigen gene leads to nontumorigenic cell lines that have a nearly normal pathway of terminal squamous differentiation and can be transformed to malignant cells by transfected Ha-ras, N-ras or Ki-ras. The combination of transfected C-myc and c-raf-I will also cause transformation to neoplastic cells that exhibit neuroendocrine traits found in small cell carcinomas. These and other results indicate that oncogenes dysregulate pathways of growth and differentiation of human bronchial epithelial cells and play an important role in human lung carcinogenesis. The molecular mechanisms of ras and raf/myc induction of neoplastic transformation is the major focus of current and future studies.