Tumor-initiating cells (TICs) have been identified as cells that account for tumor heterogeneity. Recent studies demonstrated that genes controlling stem cell biology play key roles in maintaining TICs and promote their development into cancer. Here, we review the function of nuclear receptor 3B (NR3B), a transcriptional factor that orchestrates mitochondrial function and its recently discovered roles in pluripotency. In particular, we summarize the crosstalk between NR3B and Nanog, the “stemness gene” as well as how NR3B and NR3B-regulated mitochondrial functions may command the function of Nanog as a pluripotency factor.