Five decades of nuclear transfer (NT) experiments have established a key principle in developmental genetics - despite vast functional differences, virtually all of the cells in an adult organism maintain an identical genome 1. Studies in several species have shown that the nucleus of a differentiated cell can be reprogrammed by exposure to egg cytoplasm, which re-initiates an embryonic genetic program in the transferred genome and permits the development of an identical adult organism (i.e. cloning). The demonstration that one adult cell can give rise to any other cell type has fueled tremendous interest in therapeutic applications, wherein a patient's own healthy cells would be reprogrammed to replace other cell types that have been damaged by disease or age. However, despite a half century of NT experiments in several species, the process by which genomes are reprogrammed remains largely unknown, in large part due to the inefficiency of NT and experimental limitations in manipulating the egg cytoplasm. Other, more tractable methods exist to reprogram cells from an adult to embryonic (or pluripotent) phenotype, including cell fusion 2 and direct reprogramming to create induced pluripotent stem (iPS) cells 3. In a recent report, Bhutani et al. 4 begin to shed some light into the “black box” of reprogramming (Figure 1). By demonstrating the rapid and efficient induction of pluripotency-associated genes in human fibroblasts after fusion to mouse embryonic stem (ES) cells, and the perturbation of this induction when a candidate factor (Activation-induced Cytidine Deaminase, or AID) is disrupted, the authors provide new insights into the mechanisms regulating the path to pluripotency. As importantly, in doing so, they bolster emerging evidence that AID may be involved in the elusive process of active DNA demethylation.