The recent advances in the field of molecular diagnostic techniques have led to the identification of targetable alterations prompting a paradigm shift in the management of non-small cell lung cancer (NSCLC) and an era of precision oncology. This Element highlights the most clinically relevant oncogenic drivers other than EGFR, their management and current advancements in treatment. It also examines the different challenges in resistance to targeted therapies and diagnostic dilemmas for each oncogenic driver and the future direction of NSCLC management.