The checkpoint inhibitors opened a new era in the treatment of advanced non-small-cell lung cancer (NSCLC) initially by replacing second-line standard chemotherapy with docetaxel and subsequently by replacing platinum-based chemotherapy in the first line, albeit in patients selected for a high expression of PD-L1. The decision algorithm has therefore been radically modified for patients who do not have activating mutations. However, we are only at the beginning of a new era from which we expect in the near future the use of immunotherapy in most patients as a first line treatment in substitution or in combination with chemotherapy. These strategies are now the objective of recent studies that have shown a benefit with the combination of chemotherapy and immunotherapy in patients with non-squamous histotype compared to chemotherapy alone or a benefit in patients selected for high mutational burden (TMB) with anti-PD1 and anti-CTLA-4 compared to chemotherapy alone. However, there are many questions regarding immunotherapy that should be considered in clinical practice as: response evaluation, validation of predictive factors such as TMB potentially complementary to the expression of PD-L1, proper education of the patients and of the medical staff to prompt recognition and adequate management of toxicities. In this article we discuss the current decisional algorithm and future perspectives of treatment with immunotherapy in advanced NSCLC.