Traditional signal transduction pathways appear to be operating during amphibian forelimb regeneration, as in other developing systems. A consistent picture appears to be developing that suggests that growth factors promoting proliferation during regeneration act through cAMP-independent mechanisms while factors that modulate differentiation and morphogenesis include signaling pathways in which cAMP participates. Although our understanding of these pathways is far from complete, it is becoming increasingly evident that further characterization of signal transduction events will facilitate (a) identifying major signaling substances, (b) determining the cellular events in regeneration that they modulate, and (c) defining the mechanisms through which they act. The present study demonstrates that PPtases, and in particular PTPases, can be studied in regenerating newt limbs. More importantly, this investigation demonstrates that there are progressive and significant increases in PPtase activity during regeneration. Moreover, the observed patterns of PPtase activity during regeneration conform to an emerging picture that ligands acting through receptors possessing intrinsic tyrosine kinase activity promote proliferation within the regeneration blastema. However, the substrates used in this study precluded acquiring insights about modulating effects of serine/threonine kinases (e.g., PKA and PKC). Nevertheless, these data suggest that activation of PPtases contribute to the orchestration of the diverse cellular activities required to regenerate a vertebrate appendage.