Lung cancer is the leading cause of cancer mortality worldwide. Over the past decades, the management of advanced stage lung cancer has been revolutionized from very limited options of systemic chemotherapy with limited efficacy to the present stage of testing for biomarkers (epidermal growth factor receptor (EGFR), gene mutations) to guide therapeutic decision and to improve efficacy of treatment. Relevant advancement in understanding of lung cancer biology also revealed that different lung tumours may carry different cancer driver gene mutations and thus adopt different carcinogenic pathways. These cancer driver gene mutations were found to be mutually exclusive in individual lung tumour further supporting the rationale of testing tumour sample for the presence of these mutations, especially when there could be corresponding specific agents against these molecular targets. The aim of this article is to review the current understanding of molecular targets that are important in the personalized therapy of lung cancer and how the testing for these molecular targets, namely EGFR, KRAS and ALK, will guide therapeutic decision in advanced stage lung cancer.