SCLC is the most aggressive subtype of lung cancer characterized by a remarkable response to chemotherapy followed by development of resistance. Mechanisms of initial sensitivity and of subsequent resistance are not understood. Here we highlight a broad tumor heterogeneity in mouse models of SCLC, which includes CDH1-high, primary cisplatin-resistant peripheral neuroendocrine lesions with unique metabolic and structural profile. Cisplatin treatment preferentially eliminates the CDH1-negative, more invasive secondary tumor lesions, leaving CDH1-high primary lesions relatively unaffected, thus revealing a striking differential response. Using a combined transcriptomic and proteomic approach, we found a marked reduction in proliferation and a metabolic rewiring following cisplatin-treatment. The gene expression alterations that characterize both tumor heterogeneity and cisplatin resistance indicate that the heterogeneity of SCLC tumors in the mouse is an important underlying mechanism of differential sensitivity to cisplatin. This offers perspectives for new combination therapies that might also hold promise for treating human SCLC since, given the very similar response of both mouse and human SCLC to cisplatin, similar underlying mechanisms likely apply.