Protein degradation depends on the modification of cellular targets with a small, highly conserved protein ubiquitin. Stem cells absolutely depend on protein degradation and ubiquitin modifications, referred to as ubiquitylation, to divide. Problems with ubiquitylation can result in aneuploid, potentially tumorigenic clones of stem cells, hence impeding their use in regenerative medicine. During the last year, we have used a combination of expression studies and biochemical analyses to isolate novel ubiquitylation enzymes and their substrates that are important for the accurate division of human embryonic stem cells. Our preliminary data suggest that these ubiquitylation events are pivotal for regulating transcription and the actin cytoskeleton in stem cells. By further describing the functions of these stem-cell specific enzymes and substrates in more detail, we will be able to improve the accuracy of stem cell division, thereby facilitating the expansion of stem cell clones for use in regenerative medicine or as disease models.