Recently, improved comprehension of renal cell carcinoma (RCC) pathogenesis has led to the development of small molecule targeted-drug, receptor tyrosine kinase (RTK) inhibitors such as sunitinib and sorafenib, which are now the mainstay of therapeutic options for advanced RCC patients. However, 15% of advanced RCC patients are inherently refractory to targeted-drug, and most of the remaining patients end up with drug resistance and tumor progression after 6-15 months of therapy with sunitinib, resulting in the failure to efficiently prolong the survival of RCC patients. Therefore, it is urgent to explore the potential mechanisms of targeted-drug resistance and to identify the biological markers to predict efficacy of targeted-drug in RCC. Recently, we found that long non-coding RNA (lncRNA) plays a key role in target-drug resistance of RCC, which had been published in Cancer Cell, Nature Communications and Oncogene. In this comment, we systematically reviewed our research results in targeted-drug resistance of RCC. Besides, we also share our views on future directions in targeted-drug resistance, hoping to provide implications for future study.