Based on the knowledge that microRNAs (miRNAs) are dysregulated in numerous diseases including cancer, attempts are being explored to restore or inhibit the cytosolic level and activity of clinically relevant miRNAs. Although various chemical modifications to small RNA sequences that improve activity and stability, as well as reduce toxicity, have been identified, delivery of clinically relevant miRNAs to the proper tissue in vivo remains a challenge. To overcome this challenge, innovative delivery methods using lipid-based, polymer-based, and inorganic-material-based vehicles are being developed and tested in several cell-based and in vivo systems. Additional unconventional technologies being explored for miRNA delivery include exosomal delivery, ligand-mediated delivery, mini cells, and RNA prodrugs. Herein, we present some of the limitations of conventional cancer therapeutics and how therapeutically relevant miRNAs have emerged as novel agents that overcome some of these challenges. Attention is given to the issues currently plaguing miRNA-based therapies, especially the critical barriers involved in delivering miRNAs safely, specifically, and efficiently. Importantly, some of the current efforts to overcome these barriers to advance miRNA therapeutics into the clinic are discussed.