MicroRNAs (miRNA), a class of natural RNA-interfering agents, have recently been identified as attractive targets for therapeutic intervention. The rationale for developing miRNA therapeutics is based on the premise that aberrantly expressed miRNAs play key roles in the development of human disease, and that correcting these miRNA deficiencies by either antagonizing or restoring miRNA function may provide a therapeutic benefit. Although miRNA antagonists are conceptually similar to other inhibitory therapies, restoring the function of a miRNA by miRNA replacement is a less well characterized approach. Here, we discuss the specific properties of miRNA replacement and review recent examples that explored the therapeutic delivery of miRNA mimics in animal models of cancer.