57 Lung cancer remains the leading cause of cancer-related deaths globally, but a striking shift in its demographic is emerging. The increasing incidence of lung cancer in individuals who have never smoked (LCINS) is redefining the understanding and approach to this deadly disease. The latest study published in Nature Reviews Clinical Oncology delves into the epidemiology, genetic underpinnings, and treatment paradigms of LCINS, highlighting its distinct nature from smoking-related lung cancers. Despite a global decline in smoking rates, lung cancer persists as a major health concern. In the US alone, lung cancer accounts for approximately 100,000 deaths annually. Notably, LCINS has emerged as a significant contributor to these statistics, estimated to be the fifth most common cause of cancer-related deaths worldwide in 2023 . This shift is particularly pronounced among women and individuals of Asian descent, who exhibit higher incidences of LCINS compared to other demographic groups. The study underscores the need for a paradigm shift in addressing lung cancer. While smoking cessation remains crucial, understanding the factors driving LCINS is imperative. Data suggest that the proportion of lung cancer cases in non-smokers has been steadily increasing, particularly among younger age groups and women. This trend calls for a reevaluation of lung cancer screening and prevention strategies to encompass non-smokers. LCINS exhibits distinct genetic and molecular characteristics compared to smoking-related lung cancers. The study highlights that LCINS is almost exclusively adenocarcinomas and is enriched for targetable oncogenic alterations such as EGFR mutations and ALK rearrangements . These mutations are less common in smoking-related lung cancers, indicating a different pathogenesis. Genetic predisposition plays a critical role in LCINS. Several large-scale genome-wide association studies (GWAS) have identified multiple loci associated with increased lung cancer risk in non-smokers. Additionally, germline mutations in genes such as EGFR, BRCA1, and BRCA2 have been observed in non-smoking patients, further underscoring the genetic basis of LCINS . Environmental factors such as air pollution, secondhand smoke, and radon exposure also contribute significantly to the risk of developing LCINS. The interplay between genetic susceptibility and environmental exposures necessitates comprehensive studies to elucidate the precise mechanisms driving LCINS. The biological distinctions between LCINS and smoking-related lung cancers necessitate unique diagnostic and therapeutic approaches. The study advocates for the integration of genomic profiling in the diagnostic process to identify actionable mutations. Precision oncology, which tailors treatment based on individual genetic profiles, holds promise for improving outcomes in LCINS patients. One of the critical challenges in treating LCINS is its generally poor response to conventional immunotherapy. Unlike smoking-related lung cancers, LCINS typically exhibits a low tumour mutational burden and low PD-L1 expression, markers often predictive of immunotherapy response . This highlights the need for alternative therapeutic strategies, such as targeted therapies that specifically address the oncogenic drivers prevalent in LCINS. The study also calls for broader screening initiatives, particularly in high-risk populations, to facilitate early detection and intervention. Given the rising incidence of LCINS, especially among women and younger individuals, expanding screening criteria beyond traditional smoking history could significantly impact early diagnosis and treatment outcomes. The increasing prevalence of LCINS marks a pivotal shift in the landscape of lung cancer. Future research should focus on large-scale sequencing studies to better understand the germline genetic risks and the role of environmental carcinogens. Establishing detailed registries with comprehensive exposure histories will aid in tracking epidemiological trends and identifying at-risk populations. Moreover, advancements in precision oncology and the development of novel therapeutic agents tailored to the unique biology of LCINS are crucial. Collaborative efforts between geneticists, oncologists, and public health professionals are essential to address the growing burden of LCINS and improve patient outcomes.