Variability of regenerative potential among animals has long perplexed biologists(1). On the basis of their exceptional regenerative abilities, planarians have become important models for understanding the molecular basis of regeneration(2). However, planarian species with limited regenerative abilities are also found(3,4). Despite the importance of understanding the differences between closely related, regenerating and non-regenerating organisms, few studies have focused on the evolutionary loss of regeneration(5), and the molecular mechanisms leading to such regenerative loss remain obscure. Here we examine Procotyla fluviatilis, a planarian with restricted ability to replace missing tissues(6), using next-generation sequencing to define the gene expression programs active in regeneration-permissive and regeneration-deficient tissues. We found that Wnt signalling is aberrantly activated in regeneration-deficient tissues. Notably, downregulation of canonical Wnt signalling in regeneration-deficient regions restores regenerative abilities: blastemas form and new heads regenerate in tissues that normally never regenerate. This work reveals that manipulating a single signalling pathway can reverse the evolutionary loss of regenerative potential.