Apoptosis is a precisely controlled physiological mechanism that is required for the elimination of cells during embryonic development, in response to stress and infection as well as in the maintenance of homeostasis. Since the outcome of several of these biological processes is regulated by signaling events involving tyrosine phosphorylation, members of the protein tyrosine phosphatase (PTP) gene family are expected to be of primary importance. Here, we summarize the current literature linking the activities of classical PTPs with the regulation of apoptosis. The recent discovery of caspase-cleavage mediated modulation of a member of this family, PTP-PEST, indicates that other PTPs could be modulated in a similar manner. In light of this, we present an analysis of all murine and human PTPs gene for the presence of putative caspase cleavage motifs. Additional studies linking the activity of PTPs to their own regulation during programmed cell death initiation should provide important insight into the understanding of this fundamental physiological phenomenon.