Background: Approximately 25–30% of non-small-cell lung cancer (NSCLC) patients are diagnosed when the disease is still resectable, although the risk of recurrence is significant. Recently, approaches based on targeted agents or immune checkpoint inhibitors (ICIs) have modified the management of such patients. However, some questions remain unanswered. Objectives: Our aim is to assess the current evidence on approaches involving targeted agents and ICIs in resectable NSCLC, to provide an up-to-date overview of the subject, and to identify areas of current debate, Methods: We analyzed randomized trials on ICIs and targeted therapies in early-stage NSCLC, published or presented at international oncology meetings throughout the last 5 years. Results: Osimertinib and alectinib have shown robust results in the adjuvant setting for molecularly identified patient subgroups, while ICIs have achieved robust data in the neoadjuvant/perioperative setting, with less consistent data on the pure adjuvant approach. Circulating tumor DNA levels may offer a possible biomarker for therapeutic decisions, albeit more prospective data are needed. Conclusions: Targeted agents and ICIs are revolutionizing early-stage NSCLC, similarly to what was observed in advanced disease. Prospective studies designed to compare neoadjuvant, adjuvant, and perioperative approaches and to assess the role of circulating biomarkers are warranted.