Lizard skin can produce scales during embryonic development, tail regeneration, and wound healing; however, underlying molecular signaling and extracellular matrix protein expression remains unknown. We mapped cell proliferation, signaling and extracellular matrix proteins in regenerating and developing lizard scales in different body regions with different wound severity. Following lizard tail autotomy (self-amputation), de novo scales regenerate from regenerating tail blastema. Despite topological differences between embryonic and adult scale formation, asymmetric cell proliferation produces the newly formed outer scale surface. Regionally different responses to wounding were observed; open wounds induced better scale regeneration from tail skin than trunk skin. Molecular studies suggest that neural cell adhesion molecule enriched dermal regions exhibit higher cell proliferation associated with scale growth. β-catenin may be involved in epidermal scale differentiation. Dynamic tenascin-C expression suggests its involvement in regeneration. We conclude that different skin regions exhibit different competence for de novo scale formation. While cellular and morphogenetic paths differ during development and regeneration of lizard scale formation, they share general proliferation patterns, epithelial−mesenchymal interactions and similar molecular modules composed of adhesion and extracellular matrix molecules.