AbstractAn amputated limb of an adult urodele amphibian is capable of undergoing regeneration. The new structures form from an undifferentiated mass of cells called the regenerative blastema. The cells of the blastema are believed to derive from differentiated tissues of the adult limb. However, the exact source of these cells and the process by which they undergo dedifferentiation are poorly understood. In order to elucidate the molecular and cellular basis for dedifferentiation we isolated a number of genes which are potential regulators of the process. These includeMsx‐1, which is believed to support the undifferentiated and proliferative state of cells in the embryonic limb bud; and two members of the myogenic regulatory gene family,MRF‐4andMyf‐5, which are expressed in differentiated muscle and regulate muscle‐specific gene activity. As anticipated, we find thatMsx‐1is strongly up‐regulated during the initiation of regeneration. It remains expressed throughout regeneration but is not found in the fully regenerated limb. The myogenic geneMRF‐4has the reverse expression pattern. It is expressed in adult limb muscle, is rapidly shut off in early regenerative blastemas, and is only reexpressed at the completion of regeneration. These kinetics are paralleled by those of a musclespecificMyosingene. In contrastMyf‐5, a second member of the myogenic gene family, continues to be expressed throughout the regenerative process. Thus,MRF‐4andMyf‐5are likely to play distinct roles during regeneration.MRF‐4may directly regulate muscle phenotype and as such its repression may be a key event in dedifferentiation.Myf‐5may play a role in maintaining a distinct myogenic lineage during regeneration.