CD45 is expressed on all nucleated haematopoietic cells and was originally identified as the first and prototypic transmembrane protein tyrosine phosphatase (PTPase). CD45 has been extensively studied for over two decades as a PTPase that functions in antigen receptor signaling by dephosphorylation of Src-kinases. CD45 can operate as a positive as well negative regulator of Src-family kinases. In CD45 mutant cell lines, CD45-deficient mice, and CD45-deficient human SCID patients, CD45 is required for signal transduction through antigen receptors. Our group has recently shown that CD45 can also function as a Janus kinase (JAK) tyrosine phosphatase that negatively regulates cytokine receptor signaling involved in the differentiation, proliferation, and antiviral immunity of haematopoietic cells. Moreover, a point mutation in CD45, implicated in affecting CD45 dimerization, and a genetic polymorphism that affects alternative CD45 splicing have been implicated in autoimmunity in mice and humans. CD45 is expressed in multiple isoforms and modulation of specific CD45 splice variants with antibodies can prevent transplant rejections. Moreover, loss of CD45 can affect microglia activation in a mouse model for Alzheimer's disease. Modulation of CD45 splice variants and CD45 activity might provide a unique opportunity to design drugs that turn off or turn-on antigen and cytokine receptor signaling in cancer, allergy, transplantation, or autoimmunity.