Epigenetic factors are critical regulators of biological and pathological mechanisms and they could interact with different molecular pathways. Targeting epigenetic factors has been an idea approach in disease therapy, especially cancer. Accumulating evidence has highlighted function of long non-coding RNAs (lncRNAs) as epigenetic factors in cancer initiation and development and has focused on their association with downstream targets. microRNAs (miRNAs) are the most well-known targets of lncRNAs and present review focuses on lncRNA-miRNA axis in malignancy and therapy resistance of tumors. LncRNA-miRNA regulates cell death mechanisms such as apoptosis and autophagy in cancers. This axis affects tumor metastasis via regulating EMT and MMPs. Besides, lncRNA-miRNA axis determines sensitivity of tumor cells to chemotherapy, radiotherapy and immunotherapy. Based on the studies, lncRNAs can be affected by drugs and genetic tools in cancer therapy and this may affect expression level of miRNAs as their downstream targets, leading to cancer suppression/progression. LncRNAs have both tumor-promoting and tumor-suppressor functions in cancer and this unique function of lncRNAs has complicated their implication in tumor therapy. LncRNA-miRNA axis can also affect other signaling networks in cancer such as PI3K/Akt, STAT3, Wnt/β-catenin and EZH2 among others. Notably, lncRNA/miRNA axis can be considered as a signature for diagnosis and prognosis in cancers.