Tyrosine phosphorylation is a key means of signal transduction in the immune system, initiating signals from antigen receptors, integrins, and cytokine receptors. Tyrosine phosphorylation is regulated by the balance of tyrosine kinase and tyrosine phosphatase activities. Src family kinases are prevalent in leukocytes and play critical roles in many signaling pathways present in immune cells. For example, they are the key kinases that phosphorylate both immunoreceptor tyrosinebased activation and inhibitory motifs. CD45 is a leukocyte-specific, transmembrane protein tyrosine phosphatase and an important regulator of Src family kinase activity. Here, we briefly review the importance of tyrosine phosphorylation in key signaling pathways in immune cells and then review the accumulating evidence for tyrosine phosphorylation in Toll-like receptor (TLR) signaling leading to proinflammatory cytokine and type I interferon production. We examine how tyrosine phosphorylation directly impacts TLR signaling pathways and review the involvement of specific tyrosine kinases and phosphatases. Finally, we consider how tyrosine phosphorylation signals from other signaling pathways integrate with the TLR signaling pathway to modulate proinflammatory cytokine production.