The study of regeneration has inspired centuries of scientific research. Among the many model organisms used in present days, the axolotl has become the gold standard for studying limb regeneration in vertebrates. Limb regeneration is an intricated multi-step process that involves timely regulated events such as an immune response, dedifferentiation and migration of progenitor cells, and the re-establishment of the missing structures. Although axolotl limb regeneration has long been considered a case of perfect regeneration, the mechanisms whereby a regenerated limb is able to properly integrate into the mature tissue seamlessly have long been unstudied. In this work, I have investigated how the skeletal tissue is primed to successfully regenerate and restore its functionality. To properly achieve my research, I have first sought to understand the basic appendicular skeleton biology, particularly, how the skeletal elements change with growth and age. In the first part of my thesis, I show the changes associated with growth in the zeugopodial elements, radius and ulna. A cartilaginous skeleton defines the limb during the early life stages, and ossification starts around the time the animals reach sexual maturity, a process that extends throughout their lives. In the second part of my work, I have extensively described a regeneration-induced skeletal resorption. This process is carried out by osteoclasts and it is absolutely necessary for a successful integration of the skeletal tissue. Interestingly, a direct correlation between the resorption rate and the integration efficiency could be observed. Moreover, my work provides strong evidence linking the formation of the wound epithelium with the induction of skeletal resorption and the position of resorption with blastema formation. Altogether, this work provides a comprehensive study of axolotl skeleton biology in homeostasis and regeneration, with an emphasis on how a histolytic process primes the skeletal tissue for efficient regeneration. From a comparative perspective, the understanding of the events involved in axolotl limb regeneration provides an excellent platform for evaluating how regeneration could be enhanced in non-regenerative animals, such as humans.