MRL/MpJ-Fas(lpr) mice exhibit the ability to regenerate ear tissue excised by dermal punches. This is an exceptional model to identify candidate proteins that may regulate regeneration in typically nonregenerative tissues. Identification of key molecules involved in regeneration can broaden our understanding of the wound-healing process and generate novel therapeutic approaches. Tissue profiling by matrix-assisted laser desorption ionization mass spectrometry is a rapid, powerful proteomic tool that allows hundreds of proteins to be detected from specific regions of intact tissue specimens. To identify these candidate molecules, protein expression in ear punches was examined after 4 and 7 days using tissue profiling of MRL/MpJ-Fas(lpr) mice and the nonregenerative mouse strain C57BL/6J. Spectral analysis revealed distinct proteomic differences between the regenerative and nonregenerative phenotypes, including the calcium-binding proteins calgranulin A and B, calgizzarin, and calmodulin. Spatial distributions for these differentially expressed proteins within the injured regions were confirmed by immunohistochemistry.