In metazoans, lineage-specific transcription factors and epigenetic modifiers function to establish and maintain proper gene expression programs during development. Recent landmark studies in both mouse and human have defined a set of transcription factors whose ectopic expression by retroviral transduction is capable of reprogramming a somatic nucleus to the pluripotent state. The identification of factors that are sufficient for the induction of pluripotency suggests that rewiring transcriptional regulatory networks at the molecular level can be used to manipulate cell fate in vitro. These findings have broad implications for understanding development and disease and for the potential use of stem cells in therapeutic applications.