Freshwater planarians possess remarkable regenerative abilities that make them one of the classic model organisms for the study of regeneration. These free-living members of the phylum Platyhelminthes are representatives of the simplest triploblastic organisms possessing bilateral symmetry and cephalization. Furthermore, planarians occupy an important position in the evolution of Metazoa, which allows for the possibility of vertically integrating molecular studies of regeneration in this organism to other, more widely studied animal model systems. Because of their relative simplicity, developmental plasticity, and evolutionary position, planarians are an attractive system to dissect the molecular processes underlying regeneration. The objective of this article is to present a molecular strategy to identify and functionally manipulate genes involved in the process of blastema-derived regeneration. Ultimately, the genes identified in planarians and their interactions during regeneration will define a series of useful molecular templates that may help unravel the more complex epigenetic processes of vertebrate regeneration and may perhaps uncover the factors that make regeneration permissive in some, but not all, metazoans.