E3 ubiquitin ligases, which tag specific targets with a ubiquitin molecule, play crucial roles in protein regulation necessary for a variety of cellular functions including signal transduction, protein localization, and protein degradation. Mutations in ubiquitin ligase genes have been linked to detrimental diseases like cancer or neurodegenerative disorders, however, targets, functions, and disease forming mechanisms of several ubiquitin ligases remain unknown or poorly understood. In this study, the HECT family of E3 ubiquitin ligases was characterized in the model planarian Schmidtea mediterranea. Planarians are a unique model organism with vast regenerative capabilities dependent on a population of adult pluripotent stem cells. HECT E3 genes are expressed in diverse tissues, with 11 of 18 enriched in the cycling stem cell or progeny cell populations. Novel functions for Smed-herc4-1 and Smed-wwp1 were revealed using an RNA interference (RNAi) regeneration screen. Loss of Smed-herc4-1 results in a decreased number of mitotic cells, while loss of Smed-wwp1 negatively affects tissue regeneration and leads to a loss of integrity in the animal's intestinal branches. These results are important for expanding our knowledge of HECT E3 ligases and demonstrate that planarians can be used to model the function of ubiquitin ligases in stem cells in vivo.