The treatment of non‐small cell lung cancer (NSCLC) is currently experiencing a revolution. Over the last decade, the knowledge gained about the biochemical features of biomarkers and their predictive abilities has led to the development of targeted small‐molecule inhibitors that present an alternative to harsh chemotherapy. The use of these new therapies has improved the quality of life and increased the survival of patients. The occurrence of inevitable drug resistance requires the constant development of precision medicine. The detailed understanding of the target biology and the search for innovative chemical approaches has encouraged investigations in this field. Herein, we review selected aspects of the molecular targets and present an overview of current topics and challenges in the rational development of small molecules to target NSCLC. An alternative to chemotherapy: The knowledge gained over the last decade about biomarkers and their predictive abilities has led to the development of precision medicine, which has improved the quality of life and increased the survival of patients. This Minireview highlights selected aspects of the molecular targets and presents an overview of current topics and challenges in targeting lung cancer (NSCLC).