Although amniotes (reptiles, including birds, and mammals) are capable of replacing certain tissues, complete appendage regeneration is rare. Perhaps the most striking example is the lizard tail. Tail loss initiates a spontaneous epimorphic (blastema-mediated) regenerative program, resulting in a fully functional but structurally non-identical replacement. Here we review lizard tail regeneration with a particular focus on the blastema. In many lizards, the original tail has evolved a series of fracture planes, anatomical modifications that permit the tail to be self-detached or autotomized. Following tail loss, the wound site is covered by a specialized wound epithelium under which the blastema develops. An outgrowth of the spinal cord, the ependymal tube, plays a key role in governing growth (and likely patterning) of the regenerate tail. In some species (e.g., geckos), the blastema forms as an apical aggregation of proliferating cells, similar to that of urodeles and teleosts. For other species (e.g., anoles) the identification of a proliferative blastema is less obvious, suggesting an unexpected diversity in regenerative mechanisms among tail-regenerating lizards.