Lung cancer is the leading cause of malignancy-related death in the United States and the second most common cancer diagnosis worldwide. In the last two decades, lung cancer treatment has evolved to include advances in the development of mutation-based targeting, immunotherapy, radiation therapy, and minimally invasive surgical techniques. The discovery of lung cancer as a molecularly heterogeneous disease has driven investigation into the development of targeted therapies resulting in improved patient outcomes. Despite these advances, there remain opportunities, through further investigation of mechanisms of resistance, to develop novel therapeutics that better direct the personalization of lung cancer therapy. In this review, we highlight developments in the evolution of targeted therapies in non-small cell lung cancer, as well as future directions shaped by emerging patterns of resistance.