Systemic treatment of advanced non-small cell lung cancer (NSCLC) has undergone remarkable changes in the last decade, with the introduction of targeted therapies and immunotherapy. The identification of activating mutations in the epidermal growth factor receptor (EGFR) gene (deletions in exon 19 [Del19] and point mutation L858R in exon 21) has been the first important step toward molecularly guided precision therapy in lung cancer. Several randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, and afatinib) to standard chemotherapy in first-line treatment of advanced EGFR-mutant NSCLC showed significant improvement in progression-free survival (PFS) and in response rate, with lower rates of adverse events (AEs) and better symptom control. However, none of these trials showed significant improvement in overall survival (OS). Despite impressive responses with EGFR-TKI, disease invariably progresses after 9 to 13 months, due to acquired resistance. Dacomitinib is a potent, irreversible, highly selective, second-generation EGFR-TKI, which inhibits the signaling from both heterodimers and homodimers of all the members of the human epidermal growth factor receptor (HER) family. Here, we review the clinical development of dacomitinib from phase I to phase III, with particular attention to its toxicity and on its activity on T790M mutation. Then, we critically examine the results of ARCHER 1050, a study that was crucial for Food and Drug Administration (FDA) approval. ARCHER 1050 was the first randomized phase III study comparing dacomitinib with gefitinib, in first-line treatment of patients with advanced EGFR-mutated NSCLC. Dacomitinib was superior to gefitinib in terms of primary end-point (14.7 vs 9.2 months) and OS (34.1 vs 26.8 months). The incidence of diarrhea, skin rash, mucositis and, consequently, dose reductions was higher with dacomitinib, while hepatic toxicity was higher with gefitinib. Dacomitinib constitutes one of the standard first-line options in patients with advanced EGFR-mutated NSCLC.