Molecular target therapy has been widely used in the treatment of lung cancer and other malignant tumors, and represents the mainstay of treatment for patients with advanced lung cancer. However, the emergence of drug resistance has been the main challenge for successful treatment of lung cancer. Many drug metabolism related genes and signal pathways have been implicated to be involved in drug resistance. The increasing number of studies have shown that miRNA polymorphisms associate with drug metabolism and resistance. It is believed that targeting specific miRNA expression represents a promising strategy to overcome drug resistance in lung cancer treatments. Here, we provide our up-to-date understanding of the roles of miRNAs in drug resistance of molecular target therapy, and their potential implications of lung cancer treatments.