Lung cancer remains the most common cause of cancer-related death in the United States. At presentation, the majority of patients have regional or systemic metastases and therefore require systemic therapy. For years, chemotherapy was the only systemic therapy option. A major paradigm shift has occurred in recent years with the identification of driver genetic alterations in some non-small cell lung cancers (NSCLCs). It is part of current standard of care to assess epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations in tumors of patients with advanced NSCLC. Drugs targeting these mutations provide significant clinical benefit and are the preferred therapeutic option in these patients. Ongoing clinical trials are assessing the clinical benefit from targeting other driver genetic alterations. Further therapeutic targets have been identified through greater understanding of the variety of molecular processes that facilitate tumor formation and progression. Some of these new therapeutic targets are heat shock proteins and targets that can allow enhanced anti-tumor immune response. It is expected that these advances will allow personalized management of NSCLC patients and move us away from approaching all NSCLC patients with the same therapeutic tools.