This paper reviews mutational activation of ras oncogenes and inactivation of the p53 tumor suppressor gene in human lung cancer. We discuss the frequency, type, and location of mutations in these genes in relation to known etiological factors for lung cancer. The most studied examples of these are exposure to tobacco smoke, and to radon and asbestos fibers at work. We summarize data from our laboratory on K-ras and p53 mutations in fresh tissue samples from patients with resected primary lung carcinoma whose smoking and occupational histories were known. Most of the tumors examined were histologically non-small cell carcinoma (NSCLC), mainly of the squamous cell carcinoma and adenocarcinoma types. We compare the prevalence and nature of mutations in the two histological types of NSCLC.