The ability to regenerate missing body parts is one of the great mysteries of biology and is found throughout the animal kingdom. This ability has been studied for centuries, yet satisfying explanations for how it occurs have been elusive. How do some animals regenerate and why can’t we? We aim to address this question by seeking the cellular and molecular basis for regeneration in highly regenerative organisms. Much of our work utilizes planarians, flatworms that are a classic regeneration model. To address how animals determine which tissue types to regenerate, we seek and study the instructions that guide regeneration. In planarians and acoels, we found coordinate systems of positional information guiding regeneration that involve regional expression of signaling molecules. Unexpectedly, these signaling molecules are primarily expressed in muscle. For regeneration to occur, the expression domains of the genes constituting positional information must regenerate. We discovered that signaling from the wound epidermis is required for changing gene expression in muscle to bring about the regeneration of positional information that orchestrates regeneration.