Lung cancer is the commonest cause of cancer-related death. Small cell lung cancer (SCLC) is a highly malignant neuroendocrine tumour that makes up 15-20% of the 9,700 Australians dying every year from lung cancer. Although SCLC is often sensitive to platinum-based chemotherapy at presentation, a secondary drug-resistant recurrence occurs in almost all cases, leading to a dismal overall 5-year survival rate of less than 5%. Large scale genomics analysis has revealed almost universal inactivation of TP53 and RB1, however this is always in combination with other oncogenic mutations including to the MYC family of oncogenes which is observed in around 20% of SCLC tumours. Using genetically engineered mouse models, we determined the efficacy of MYC to initiate SCLC from discrete lung cell lineages. Using this model, we showed that overexpression of MYC in combination with the loss of Trp53 and Rb1 specifically in neuroendocrine cells or broadly throughout the lung epithelium results in SCLC with a dramatically different transcriptomic profile. These data suggest that additional non-neuroendocrine cells can give rise to SCLC with transcriptomic profile observed in a subset of patients. These mouse models may aid in testing for new treatment options for SCLC patient subgroups.