Vera Hirsh McGill Department of Oncology, Royal Victoria Hospital, Montreal, QC, Canada Abstract: Until recently, few treatment options existed for the treatment of squamous cell carcinoma (SqCC) of the lung, especially in the second-line setting following platinum-based chemotherapy. Accordingly, outcomes in this subtype of non-small-cell lung cancer (NSCLC) were generally poor. In this context, the recent availability of the checkpoint inhibitors nivolumab and pembrolizumab, the anti-VEGFR2 antibody ramucirumab (combined with docetaxel), and the ErbB-family blocker afatinib for the treatment of relapsed/refractory SqCC of the lung represent major advances. However, the rapid expansion of the treatment armamentarium invites many questions regarding optimal treatment choice and sequence in individual patients. This review focuses on the biologic rationale and clinical evidence to support the use of afatinib in this treatment setting, highlighting the prominent role of the ErbB-signaling cascade in SqCC tumors. The seminal Phase III LUX-Lung 8 study, on which the approval of afatinib is based, is discussed and contextualized with the emergence of immunotherapies. Finally, criteria are explored that might drive physicians’ treatment decisions when considering the use of afatinib based on individual patient characteristics. Other ongoing developments in the treatment of SqCC of the lung that will lead to further options and welcome improvements in the management of this difficult-to-treat disease are summarized.Keywords: squamous cell carcinoma of the lung, afatinib, LUX-Lung 8, EGFR, ErbB