Progression from a treatment-sensitive to a treatment-resistant tumor state is a virtually universal phenomenon in patients with small-cell lung carcinoma (SCLC). In such individuals, this tumor progression may involve transitions from a SCLC to a non-SCLC lung cancer phenotype. We are investigating the cell and molecular biology aspects of these transitions and have derived a cell culture model of one such change, oncogene-induced transition of SCLC to the large-cell undifferentiated lung cancer phenotype. Here we discuss the potential implication of this model for understanding the cell lineage and molecular events regulating normal bronchial epithelial cell differentiation and their relationships to the histogenesis and behavior of lung cancers.