The Myc protein family are important cancer causing factors, but also have critical roles in normal stem cells including both human ES and iPS cells. However, the mechanisms by which Myc acts in both cancer cells and in iPS and ES cells are not well understood. Here we examined Myc function in human ES cells finding that the two main Myc family members, c-Myc and N-Myc, are both required for human ES cell growth. We further investigated Myc function in human ES cells by conducting the first ever genomics studies on Myc in human ES cells. Myc binds two main classes of genes in human ES cells–those that promote a stem like state and those that promote differentiation–with different consequences. Myc appears to turn on the stemness genes and turn off the differentiation genes. The function of Myc to turn off differentiation genes has long been postulated but the mechanism has remained elusive with most research focusing on Myc’s function to turn genes on instead of off. We found using genomics studies that Myc relies on a novel cofactor called Miz-1 to repress the differentiation genes. Our studies were the first genomics studies on Miz-1 in any cell type. Overall these studies shed important light on how Myc functions in human ES cells to promote pluripotency via its cofactor Miz-1.