Over the last decade, the introduction of specific antibodies directed against the programmed death (PD-1) receptor, its ligand PD-L1 (programmed death ligand-1), and the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) receptor into the therapeutic armamentarium for patients with metastatic non-small-cell lung cancer (mNSCLC) led to unprecedented improvements in the survival of a proportion of patients.1 While these immune checkpoint inhibitors (ICIs) were initially evaluated as monotherapy in the second-line setting, more recent clinical trial data have moved these agents to the first-line setting, either as monotherapy or in combination regimens. In fact, it is fair to say that nearly all patients with non-oncogene driven mNSCLC nowadays receive an anti PD-(L)1 based treatment in first line. This article will briefly summarize the available clinical trial data with this therapeutic strategy after which the challenge of choosing the best immunotherapeutic option for the individual patient will be addressed.