Small molecules can greatly enhance the efficiency of induced pluripotent stem (iPS) cell generation, but the mechanisms by which they act have not been fully explored. We show here that a cocktail of three small molecules significantly promotes iPS cell generation from human fibroblasts. Our data indicate that the small molecule cocktail substantially upregulates the production and stability of a specific microRNA cluster, miR302/367. Collectively, our findings suggest that the small molecule cocktail promotes reprogramming at least partly through the induction of the miR302/367 cluster expression. Further insights into this process may pave the way for the generation of iPS cells using only small molecule cocktails.