Most mammals cannot easily overcome degenerative disease or traumatic injuries. In contrast, an innate ability to regenerate is observed across animal phyla. Freshwater planarians are amongst the organisms that are capable of stem cell-mediated whole-body regeneration and have served as an exemplary model to study how pluripotency is maintained and regulated in vivo. Here, we review findings on the role of post-translational modifications and the genes regulating phosphorylation, ubiquitylation, and chromatin remodeling in planarian regeneration. Furthermore, we discuss how technological advances for identifying cellular targets of these processes will fill gaps in our knowledge of the signaling mechanisms that underlie regeneration in planarians, which should inform how tissue repair can be stimulated in non-regenerative model organisms and in humans.