Regeneration and tissue repair are widely spread in the animal kingdom, and actually present in many phyla, although with surprisingly different efficiencies within a given phylum [1]. Moreover, even though most regenerative processes depend on blastema formation, i.e. proliferation of mesenchymal cells in the vicinity of the amputation plane, the ways to achieve this process are multiple (Fig. 1). In fact, the questions linked to the phenomena of regeneration and tissue repair are numerous, and each forms in itself one piece of this amazing puzzle for biologists to reconstitute. Some of those are listed here: Where is the boundary between regeneration and tissue repair? How much does tissue repair impinge on regeneration? What are the mechanisms that control cell proliferation in cases where a blastema is formed and where it does not? Are these mechanisms conserved across evolution? Where are the differences between the mechanisms that control cell proliferation in blastemas and those that control cell proliferation in oncogenic tumors? Are the regenerative processes leading to the replacement of amputated structures close to embryonic/fetal developmental processes, or do they rather represent distinct adult developmental processes ? What are the memory mechanisms that allow the reactivation of an embryonic/fetal/larval developmental program? What are the criteria that distinguish regeneration in closely related species such as in the neotenic axolotl or in the postmetamorphic newt? Is it possible to consider appendage regeneration in a larval-stage animal as a short memory process, i.e. memory of a recently achieved developmental process, whereas that occurring in adult animals would involve a long memory process? At the other extremity of the life cycle, what are the links between the regeneration potential and the ageing process in a given species? These questions are fundamental biological questions, and their understanding will open new avenues to regenerative medicine. An important prerequisite, however, is systematic comparative functional analyses of the various regenerative modes at hand in vertebrates as well as invertebrates. In this issue we propose to approach some of these questions through a variety of angles and model systems.