The protein tyrosine phosphatase (PTP) CD45 is abundantly expressed on all nucleated hematopoietic cells and is critical for classical antigen receptor signalling indicated by the arrested development of B and T cells in mice deficient for CD45. Despite its clear role in positive regulation of signalling through the activation of the Src family of tyrosine kinases, many reports have shown CD45 to also negatively regulate this process. Given such a dichotomy in CD45 function and a poor understanding of the mechanism underlying the phenotype of CD45(-/-) lymphocytes, we considered it timely to review the existing data and attempt to determine whether aspects of the CD45(-/-) phenotype result from excessive positive or negative kinase activity and the target molecules that may mediate such effects.