Despite recent advances in understanding the cancer signaling pathways and in developing new therapeutic strategies, non-small cell lung cancer (NSCLC) shows grim prognosis and high incidence of recurrence. Insufficient dis- ruption of oncogenic signaling and drug resistance are the most common causes of tumor recurrence. Drug resistance, in- trinsic or acquired, represents a main obstacle in NSCLC therapeutics by limiting the efficacy both of conventional che- motherapeutic compounds and new targeted agents. Therefore, novel and more innovative approaches are required for treatment of this tumor. MicroRNAs (miRNAs) are a family of small non-coding RNAs that regulate gene expression by sequence-specific targeting of mRNAs causing mRNA degradation or translational repression. Accumulating evidence suggests that impairment of candidate miRNAs may be involved in the acquisition of tumor cell resistance to conventional chemotherapy and novel biological agents by affecting the drug sensitivity of cancer cells. The modulation of these miR- NAs, using antagomiRs or miRNA mimics, can restore key gene networks and signaling pathways, and optimize anti- cancer therapies by inhibition of tumor cell proliferation and increasing the drug sensitivity. Therefore, miRNA-based therapeutics provides an attractive anti-tumor approach for developing new and more effective individualized therapeutic strategies, improving drug efficiency, and for predicting the response to different anticancer drugs. In this review, we pre- sent an overview on the role of miRNAs in resistance mechanisms of NSCLC, discussing the main studies on the aberra- tions in apoptosis, cell cycle and DNA damage repair pathways, as well as in novel drug targets.