The utility of RNA interference in therapeutic applications depends on effective delivery of highly potent molecules. While therapeutic applications of RNAi have historically been focused on introduction of siRNA molecules, microRNAs (miRNAs) have emerged as another important arena for therapeutics. miRNAs regulate gene expression through both translational attenuation and message RNA cleavage and have been shown to be important in many biologies including development, differentiation, and disease. Just as the performance of an siRNA molecule in vivo is heavily dependent upon its design, the design of miRNA inhibitors and miRNA mimics must be optimized for in vivo applications. Here we will discuss design considerations for the stability and potency of miRNA mimic molecules. We show that stabilized miRNA mimic molecules lose functionality compared to our standard miRNA mimic molecules due, in part, to the activity of the stabilized passenger strand acting as a miRNA inhibitor. We will discuss how mismatches affect the activity of the stabilized miRNA mimics, perhaps by generating a passenger strand that is less functional as an inhibitor molecule.