Amputated tails of lizards regenerate while limbs form scars which histological structure is very different from the original organs. Lizards provide useful information for regenerative medicine and some hypotheses on the loss of regeneration in terrestrial vertebrates. Analysis of tail and limb transcriptomes shows strong downregulation in the tail blastema for immunoglobulins and surface B and T receptors, cell function, and metabolism. In contrast, in the limb blastema genes for myogenesis, muscle and cell function, and extracellular matrix deposition but not immunity are variably downregulated. The upregulated genes show that the regenerating tail is an embryonic organ driven by the Wnt pathway and non-coding RNAs. The strong inflammation following amputation, the non-activation of the Wnt pathway, and the upregulation of inflammatory genes with no downregulation of immune genes indicate that the amputated limb does not activate an embryonic program. Intense inflammation in limbs influences in particular the activity of genes coding for muscle proteins, cell functions, and stimulates the deposition of dense extracellular matrix proteins resulting in scarring limb outgrowths devoid of muscles. The present study complements that on upregulated genes, and indicates that the regenerating tail requires immune suppression to maintain this embryonic organ connected to the rest of the tail without be rejected or turned into a scar. It is hypothesized that the evolution of the adaptive immune system determined scarring instead of organ regeneration in terrestrial vertebrates and that lizards evolved the process of tail regeneration through a mechanism of immuno-evasion.