In many mouse models of skin cancer, only a few tumors typically form even though many cells competent for tumorigenesis receive the same oncogenic stimuli. These observations suggest an active selection process for tumor-initiating cells. Here, we use quantitative mRNA- and miR-Seq to determine the impact ofHrasG12Von the transcriptome of keratinocytes. We discover thatmicroRNA-203is downregulated byHrasG12V. Using a knockout mouse model, we demonstrate that loss ofmicroRNA-203promotes selection and expansion of tumor-initiating cells. Conversely, restoration ofmicroRNA-203using an inducible model potently inhibits proliferation of these cells. We comprehensively identifymicroRNA-203targets required forHras-initiated tumorigenesis. These targets include critical regulators of theRaspathway and essential genes required for cell division. This study establishes a role for the loss ofmicroRNA-203in promoting selection and expansion ofHrasmutated cells and identifies a mechanism through whichmicroRNA-203antagonizesHras-mediated tumorigenesis.