Protein tyrosine phosphorylation is involved in the regulation of every facet of biological phenomena. Signal transduction mechanisms operative in lymphocyte development, activation, and differentiation have been studied intensively, and are also found to support this premise. In this review, I focus on the crucial problems surrounding CD45, a prototypic receptor-type protein tyrosine phosphatase (RPTP) of the immune system: (1) the role of CD45 for antigen receptor-initiated signaling in T and B cells, (2) the physiological relevance of CD45 isoforms, (3) potential regulatory mechanisms of CD45 PTP activity, and (4) the clinical significance of structural abnormalities in PTP. Furthermore, other PTPs that may be important to the exquisite functioning of the immune system are reviewed.