Diagnostic and treatment algorithms in non-small cell lung cancer (NSCLC) are evolving at a never-before-seen pace. Histological subtyping to maximise treatment efficacy and avoid toxicity has marked the beginning of the revolution, opening the way to molecular characterisation to guide genomically driven treatments with targeted agents, led by an Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) inhibitors. More recently, agents against the Program Death 1 receptor (PD-1) and ligand 1 (PD-L1) have entered the clinical arena, offering new hope to NSCLC patients, although several uncertainties remain to be elucidated. Here, we review the most clinically relevant advances in the diagnosis and treatment of NSCLC in the past decade.