THE tyrosine kinase Syk (relative molecular mass 72,000), which is widely expressed in haematopoietic cells, becomes associated with and activated by engagement of the B-cell antigen receptor^1,2. Furthermore, it has been implicated in signalling through the receptors for interleukin-2 (IL-2)³, granulocyte colony-stimulating factor (G-CSF)⁴ and Fc⁵, the T cell receptor, as well as through receptors for several platelet agonists⁷. A homologous kinase, ZAP-70, is crucial in signalling through the T-cell receptor and in T-cell development^8,9. Using homologous recombination in embryonic stem cells, we created mice null for the syk gene which showed petechiae in utero and died shortly after birth. Irradiated mice reconstituted with Syk-deficient fetal liver showed a block in B-cell development at the pro-B to pre-B cell transition, consistent with a key role for Syk in pre-B-cell receptor signalling. Despite the production of small numbers of immature B cells, Syk-deficient radiation chimaeras failed to accumulate mature B cells, indicating a possible role for this protein in the production or maintenance of mature B cells. In addition, whereas the development of αβ T cells proceeded normally, Syk-deficient mice showed impaired development of thymocytes using the Vγ3 variable region gene (Vγ3⁺ thymocytes). Finally, we show that Syk is not required for signalling through the IL-2 and G-CSF receptors.