The molecular mechanisms underlying whole-body regeneration are best understood in the planarian flatworm Schmidtea mediterranea, where a heterogeneous population of somatic stem cells called neoblasts provides new tissue for regeneration of essentially any missing body part. Studies on Schmidtea have provided a detailed description of neoblasts and their role in regeneration, but comparatively little is known about the evolutionary history of these cells and their underlying developmental programs. Acoels, an understudied group of aquatic worms that are also capable of extensive whole-body regeneration, have arisen as an attractive group to study the evolution of regenerative processes due to their phylogenetically distant position relative to flatworms. Here, we review the phylogenetic distribution of neoblast cells and compare their anatomical locations, transcriptional profiles, and roles during regeneration in flatworms and acoels to understand the evolution of whole-body regeneration. While the general role of neoblasts appears conserved in species separated by 550 million years of evolution, the extrinsic inputs they receive during regeneration can vary, making the distinction between homology and convergence of mechanism unclear. A more detailed understanding of the precise mechanisms behind whole-body regeneration in diverse phyla is necessary to understand the evolutionary history of this powerful process.