The survival rate of cancer patients has increased considerably in the last 20 years owing to significant efforts made in prevention, early detection protocols, combined chemotherapy regimens, targeted therapies, refined radiotherapy and cancer vaccines. However, metastasis and acquired resistance to current therapies represent two major challenges for achieving long-term cure. Therefore, new treatment strategies must be developed. One promising alternative is epigenetic-based therapies, of which miRNAs are at the forefront. MicroRNAs are endogenous small non-coding RNAs, often deregulated in cancer, which regulate gene expression by specific binding to the 3′-UTR of target genes. They are excellent candidates for therapy since miRNAs can regulate multiple targets of the same or different pathways, thereby minimizing the risk of resistance development or compensatory mechanisms. In this review, the mechanisms that lead to miRNA deregulation in cancer, their feasibility as therapeutic tools and the different strategies for the pharmacological manipulation of miRNAs in preclinical animal models are discussed.