Abstract: The availability of several EGFR TKIs for the treatment of EGFR mutation-positive NSCLC poses important questions regarding the optimum sequence of therapy. A key consideration is how best to use the third-generation TKI, osimertinib. While osimertinib has demonstrated impressive efficacy and tolerability in a first-line setting, there are currently no standard targeted treatment options following progression. There is an argument, therefore, for reserving osimertinib for second-line use in patients who acquire the T790M resistance mutation after first- or second-generation TKIs. This article reviews recent clinical studies that have assessed the activity of sequential EGFR TKI regimens. These studies support the hypothesis that sequential use of EGFR TKIs represents a viable treatment option in ‘real-world’ clinical practice.