The first-line treatment of choice for patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is an EGFR tyrosine kinase inhibitor, of which five are predominantly available in practice: gefitinib, erlotinib, afatinib, dacomitinib and osimertinib. The vast majority of prospective clinical trial data with these agents is limited to patients with the common activating and sensitizing EGFR mutations: exon 19 deletions and exon 21 L858R point mutations. However, 10%‒20% of NSCLC patients harbor uncommon EGFR mutations which have variable sensitivity to different EGFR TKIs. Owing to their molecular structures, afatinib, dacomitinib and osimertinib have broader inhibitory profiles than the first-generation agents, gefitinib and erlotinib. Nevertheless, the paucity of prospective clinical data, the wide heterogeneity of uncommon mutations and the existence of compound mutations in up to 25% of cases complicate treatment decisions in this patient subgroup. Here, we collate the latest preclinical and clinical data regarding the activity of different TKIs against major uncommon EGFR mutations including compound mutations, but excluding exon 20 insertions which are generally insensitive to TKIs. Based on these data, we offer suggestions regarding treatment strategies for uncommon EGFR mutations. Moving forward, it will be important to include uncommon EGFR mutations in the first-line molecular analysis of all patients with adenocarcinoma of the lung, as this will help optimize patient outcomes according to their precise genotype.