Tobacco smoking is the most common cause of lung cancer, but approximately 10-25% of patients with lung cancer are life-long never smokers. The cause of lung cancer in never smokers is unknown, although tobacco-smoke exposure may play a role in some of these patients. Lung cancer that develops in the absence of significant tobacco-smoke exposure appears to be a unique disease entity with novel genomic and epigenomic alterations and activation of molecular pathways that are not generally seen in tobacco-smoke-induced lung cancer. These molecular alterations are very likely responsible for the unique clinico-pathological features of lung cancer in never smokers (LCINS), and some of these molecular alterations - such as the activating EGFR TK mutations and EML4-ALK fusion - significantly influence therapeutic choices and treatment outcomes. In the last few years there has been a number of studies exploring the molecular characteristics of LCINS, and some of them have reported new and significant findings. Here we review the key findings from these studies and discuss their potential therapeutic implications.