The excellent systematic review by Dr Huang et al leaves us grappling with questions about the role of adjuvant EGFR TKIs in lung cancer. Have we chosen the right TKI? Neither gefitinib nor erlotinib has shown a survival advantage in advanced NSCLC; however, the irreversible inhibitor afatinib demonstrated a survival benefit in advanced NSCLC with exon 19 deletions. What is the optimal duration of adjuvant TKI therapy? Is 2 years enough time to see the full benefits? Recurrences largely occurred while not receiving TKI treatment in the SELECT study, suggesting that 2 years may be inadequate. Most recurrences were still sensitive to reversible TKIs, which suggests that TKIs suppress sensitive clones but do not eliminate them. Will adjuvant TKI therapy require continuous dosing, similar to imatinib for chronic myelogenous leukemia, or will benefits be seen within a limited time frame, such as occurs with adjuvant tamoxifen treatment for breast cancer? What is the optimal dose that most patients will tolerate or do adjuvant TKIs need to be given at full dose? Although the incidence of T790M mutations account for one-half of acquired resistance with the reversible TKIs, T790M mutations are not the major reason for relapse off of TKI adjuvant therapy. Are third-generation TKIs (eg, osimertinib), which target T790M, appropriate or better choices for adjuvant therapy? The improved tolerability of third-generation TKIs could increase compliance even if T790M is not a major cause for relapse. With the rapid advances in cell-free DNA technologies, we are able to detect somatic mutations in blood with a high degree of sensitivity and specificity. We could use highly sensitive platforms to monitor patients postoperatively to detect minimal residual disease. These assays could be used in designing clinical trials for monitoring recurrence postoperatively to modify therapy at the time of molecular recurrence. The use of such methods to detect minimal residual disease could potentially better select patients postoperatively for adjuvant EGFR TKI therapy.