MicroRNAs (miRNAs) are a class of endogenous non-coding RNAs that post-transcriptionally co‐regulate networks of genes. The evolutionary history of miRNAs suggests they may play major roles in cell state transitions during the development of complex organisms. Here we characterized the functional role of miRNAs in the generation of induced pluripotent stem cells (iPSCs) from fibroblasts. We found that miRNAs specifically and endogenously expressed in embryonic stem cells (ESCs), including miR-294 and miR-302, greatly enhance the frequency, rate and specificity of fibroblast de-differentiation into iPSCs. Further, the Let-7 miRNAs, a family endogenously expressed in fibroblasts, are potent inhibitors of this same transition. Unexpectedly, a genome-wide screen revealed that the miR-181 family, normally activated in differentiating ESCs, also enhances de-differentiation. To determine the mechanisms by which these miRNA families enhance de-differentiation we developed unbiased high-throughput techniques for identifying and functionally characterizing candidate miRNA targets during this transition. We identified twenty‐six miR‐294 and miR‐181 target genes that act as barriers to de-differentiation, many with cooperative relationships. We further found that both miR‐294 and miR‐181 co-regulate Wnt and TGF‐Beta signaling, with miR-294 additionally regulating Akt signaling. TGF‐Beta inhibition cooperated with Akt or Wnt Activation to enhance iPSC generation. We also identified miR‐294 as a strong inhibitor of the epithelial-to-mesenchymal transition, a known barrier to de-differentiation. These data establish miRNAs as potent regulators of somatic cell reprogramming, demonstrate that single miRNAs act through co‐inhibition of many genes, generate the most comprehensive functionally determined miRNA‐mRNA networks to date, and elucidate interactive relationships among genes that normally suppress de-differentiation.