Although the incidence of lung cancer has decreased due to the reduction of tobacco use, lung cancer remains the leading cause of cancer-related death. Lung squamous cell carcinoma represents 30% of lung cancers and only recently have possible drug-targetable mutations been identified in this disease, including fibroblast growth factor receptor 1 (FGFR1) gene amplification and genetic alterations in the phosphoinositide-3 kinase pathway. These discoveries have generated a great interest in the clinic and the initiation of clinical trials using FGFR tyrosine kinase inhibitors to treat FGFR-altered lung cancers. However, preliminary results from these studies have shown that not all patients respond to therapy. Here we review current unresolved questions on the selection of patients for their recruitment in FGFR tyrosine kinase inhibitor trials, how FGFR inhibitors could be combined with other targeted therapies or immunotherapies to improve patient outcome, and how the current preclinical models can help address these questions.