Epidermal growth factor receptor (EGFR) and v-Ki-ras 2 (KRAS; viral Kirsten rat sacoma 2 oncogene homolog) oncogenes are predictors of response to EGFR-targeted therapy in lung carcinomas. Morphologic heterogeneity of lung carcinomas is reflected at the molecular level and may confound interpretation of immunohistochemistry, fluorescence in situ hybridization, and mutational assays, which are all used for analysis of KRAS and EGFR genes. Furthermore, molecular characteristics may differ between the primary tumor and corresponding metastases. The aim of this study was to determine if the KRAS and/or EGFR status of primary and metastatic lung carcinoma differs. Three hundred thirty-six cases of primary lung carcinomas were tested for EGFR and KRAS, and 85 cases had a metastasis (25%). Of the 40 cases (47%) with sufficient material for EGFR and KRAS mutational analysis, there were 11 (27.5%) primary tumors and 4 (10%) metastases identified with a KRAS mutation. Of the cases with EGFR fluorescence in situ hybridization results, there were 3 (8%) primary tumors and 8 (24%) metastases that were fluorescence in situ hybridization positive. Overall, there were 9 cases (22.5%) with discordant KRAS status and 11 cases (32.5%) with discordant EGFR fluorescence in situ hybridization status. Our results suggest that the EGFR and KRAS status of primary lung carcinomas may not predict the status in the corresponding metastases. This observation may have important implications for molecular testing for targeted therapies.