The diagnosis and treatment of large cell neuroendocrine carcinoma are controversial, difficult, and clearly still evolving. Diagnosing this particular entity can be hampered by the limitations and restrictions imposed by its own definition in the current WHO classification. These complexities in the semantics of diagnostic criteria can puzzle not only the pathologist but also the treating physician, and lead to difficulties in choosing treatment for individual patients. Because of its low incidence (2%-3% of non-small cell carcinomas) and the difficulties in diagnosis, data regarding treatment outcomes are based on series in which the diagnosis is frequently made retrospectively in reclassification, the numbers of patients are small, and the determinants of therapy choice (e.g., treatment with or without adjuvant chemotherapy postresection) cannot be known. Thus, the evidence on which to base recommendations for stage-based treatment paradigms is flawed in many respects. This article discusses these difficult issues for pathologists and oncologists, offers a perspective regarding approaches in treatment, and suggests ways in which prospective data on this uncommon cancer can be gathered to inform treatment guidelines and improve patient outcomes.