Simple SummaryLung cancer remains the most commonly diagnosed cancer in the United States, only behind sex-specific cancers such as breast and prostate cancer. While not a sex-specific cancer, lung cancer exhibits sex-specific trends. Males are generally at a higher lifetime risk of developing lung cancer and have a higher mortality than females. There are also differences in therapeutic response between the sexes. As lung cancer is a complex disease, this difference is likely a combination of environmental factors, such as environmental exposures, diet, and smoking status, with inherent biological differences, such as the contribution of sex hormones and differences in immune responses. This narrative review focuses specifically on these biological differences and their contributions to this difference. Gaining a better understanding of the biological reasons behind this sex difference could lead to better treatment and screening decisions in the clinic that take the biological sex of the patient into consideration.AbstractSex disparities in the incidence and mortality of lung cancer have been observed since cancer statistics have been recorded. Social and economic differences contribute to sex disparities in lung cancer incidence and mortality, but evidence suggests that there are also underlying biological differences that contribute to the disparity. This review summarizes biological differences which could contribute to the sex disparity. Sex hormones and other biologically active molecules, tumor cell genetic differences, and differences in the immune system and its response to lung cancer are highlighted. How some of these differences contribute to disparities in the response to therapies, including cytotoxic, targeted, and immuno-therapies, is also discussed. We end the study with a discussion of our perceived future directions to identify the key biological differences which could contribute to sex disparities in lung cancer and how these differences could be therapeutically leveraged to personalize lung cancer treatment to the individual sexes.