The introduction of first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib and afatinib) for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC) has dramatically improved patients' prognosis and quality of life (QoL). Unfortunately, after an initial and sometimes durable benefit from EGFR-TKI therapy, all patients with EGFR-mutant lung cancer eventually become resistant to the treatment and experience disease progression. In approximately 50% of these patients, genomic alterations in the EGFR kinase domain resulting in the mutant T790M are responsible for the resistance and this has led to the development of novel EGFR inhibitors active against mutant-T790M EGFR. The remaining 50% of patients with acquired resistance (AR) to EGFR-TKIs do not harbour the T790M mutation. In these cases, other mechanisms are involved in the development of AR such as perturbations of downstream pathways (e.g. K-RAS mutations), activation of alternative bypassing pathways (including c-Met, AXL, PIK3CA, BRAF), or histologic transformation. This review summarizes the main treatment strategies for this particular and heterogeneous group of "T790M-negative" patients.