Pembrolizumab is a humanized monoclonal antibody against PD-1 capable of enhancing antitumor immune activity. The KEYNOTE-001 study showed that pembrolizumab has activity in advanced non-small-cell lung cancer patients and identified programmed death ligand 1 (PD-L1) as a companion test to select patients most likely to benefit from pembrolizumab. Five randomized clinical trials showed the efficacy of pembrolizumab in non-small-cell lung cancer: in second-line setting PD-L1 ≥1% (KEYNOTE-010), in first-line setting PD-L1 ≥50% (KEYNOTE-024 and KEYNOTE-042) and in first-line setting in combination with platinum doublets, any expression of PD-L1 (KEYNOTE-189 and KEYNOTE-407). Future challenges are the identification of the role of pembrolizumab in adjuvant, neoadjuvant, locally advanced disease or oncogene-addicted patients, in combination with radiotherapy or other biological agents.