The optimal treatment sequence for patients with metastatic epidermal growth factor receptor (EGFR) mutation-positive (EGFR-M+) non–small-cell lung cancer (NSCLC) continues to evolve, related largely to an increasing number of breakthroughs and studies in the field. The efficacy of tyrosine kinase inhibitors in the treatment of these patients is well established; however, the treatment decision-making process is becoming more complex as our knowledge of EGFR mutations and resistance pathways grows and more treatment options become available. Thus, treating physicians must consider an increasing number of factors. We present a stepwise approach to personalizing the treatment of patients with EGFR-M+ NSCLC, emphasizing some of the real world challenges faced by treating physicians. We reviewed the decision criteria for selecting the best first-line therapy, highlighted the importance of repeat biopsy on disease progression to determine the most appropriate next-line therapy, and discussed the options for third-line therapy and beyond. We also present an algorithm designed to optimize the sequencing strategies for prolonging survival and maintaining quality of life in our patients with EGFR-M+ NSCLC.