Src-family kinases and Syk tyrosine kinases have crucial roles in multiple leukocyte intracellular signaling pathways. In immunoreceptor-related pathways, these enzymes work together sequentially, with Src-family kinases phosphorylating specific protein substrates, which in turn recruit and activate Syk. Recent evidence indicates that several non-immunoreceptors also use Src-family kinases and Syk in this same fashion. In leukocyte integrin signaling, the interaction between the kinases is more complex, where they appear to act in a sequential manner but the mechanisms by which they are activated remain poorly defined. Elucidating the regulation of these tyrosine kinase-based signaling pathways in leukocytes remains an important goal in understanding how immune cells respond to the multitude of activating agents they encounter.