The molecular characterization of lung cancer has considerably changed the classification and treatment of these tumors, becoming an essential component of pathologic diagnosis and oncologic therapy decisions. Through the recognition of novel biomarkers, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocations, it has been possible to identify subsets of patients who benefit from targeted molecular therapies. The success of targeted anticancer therapies and new immunotherapy approaches has created a new paradigm of personalized therapy and has also led to accelerated development of new drugs for lung cancer treatment. This paradigm change affects all stakeholders in the fight against lung cancer including pathologists. Currently, several multiplex genotyping platforms for the detection of oncogene mutations, gene amplifications, and rearrangement are moving to the clinical setting. Genome-wide molecular investigations using next-generation sequencing (NGS) technologies have been evaluated in the research setting, with promising results.