ABSTRACT Small cell lung carcinoma (SCLC) is one of the most intractable human cancers to cure. It is an aggressive tumor characterized by rapid growth, metastatic progression, and initial response followed by almost invariable resistance to therapy. Studies to date have not resolved the extent that diverse genetic and epigenetic programs drive SCLC and contribute to its lethality. We combined one of the largest and most diverse inventories of patient-derived xenograft models of SCLC globally with an ex vivo culture system that maintains transcriptional fidelity with matched primary SCLC tumor to identify distinct and dynamic phenotypic states that differ in functional attributes within individual tumors. We show that human SCLC tumors display distinctive equilibria in the proportion of cells in various phenotypic (not merely transcriptional) states. We also show that SCLC states are highly regulated by multivalent cellular plasticity and we measure the kinetics of this plasticity at the single cell level. Importantly, standard of care chemotherapies in this disease preferentially kill specific cancer cell states. In this proposal, we posit that understanding the facets of SCLC's intratumoral heterogeneity will: 1) contribute to our understanding of a poorly characterized aspect of cancer heterogeneity; 2) reveal how stochasticity and/or ecological cues in single-cell behaviors promote phenotypic equilibrium in cancer populations; 3) provide insight into the biological and clinical behavior of SCLC; and 4) advance desperately needed new therapeutic strategies of epigenetic reprogramming in this recalcitrant disease. Our team of investigators have content expertise in several computational, experimental, and translational methods pertinent to this proposal including human-derived in vivo and ex vivo model systems, single-cell RNA sequencing, bulk genetic and expression analysis, single cell fluorescence tracking, and mathematical and statistical modeling. Our integrative approach is poised to formulate and validate a unified model of cellular states and program diversity in SCLC. If successful, the characterization of malignant cell ontogenic programs (SA1), their plasticity (SA2), and the advancement of new therapies designed to combat plasticity by epigenetic reprogramming (SA3) will advance a unique scientific canvas for the study of this highly lethal disease.