In addition to the antigen receptors, other molecules contribute to cell activation: first, by functioning as coreceptors (eg, CD4, CD8, CD19/CD21); second, by increasing the avidity of the interaction with antigen or the antigen-presenting cell (eg, LFA-1); or, third, by inducing separate signal transduction events that influence the cellular response (eg, CD28, CD40). Coreceptors, such as CD4 or CD8 in T cells or CD19/CD21 in B cells, are of particular interest in the context of antigen receptor signal transduction, since they directly contribute to the formation of the complex between the antigen receptor and the antigen complex, thereby increasing the sensitivity of the interaction. The coreceptors also contribute to the initiation of signals, as we will discuss below. Protein-tyrosine phosphorylation is important in the initiation of cellular responses by antigen receptors on either E3 or T cells. Neither the TCR nor the B cell antigen receptor (BCR) has intrinsic PTK activity. Both appear to activate cytoplasmic PTKs, although at least one tyrosine phosphatase, CD45, is also important in regulating antigen receptor-induced signal transduction. Members of two distinct classes of PTKs, of the Src family and of the Syk/ZAP-70 family, have been implicated in TCR and BCR signal transduction. These distinct PTKs interact with the TCR and BCR as well as with each other. The events downstream of protein-tyrosine phosphorylation following TCR or BCR stimulation include the activation of the phosphatidylinositol pathway, activation of Ras, and activation of several serinelthreonine protein kinases and phosphatases. These events have been causally related to a variety of responses, of which the best characterized is the transcriptional induction of the interleukin 2 (IL-2) gene in T cells. Our understanding of the detailed intermolecular connections between the early events and later cellular responses is rapidly evolving. The interpretation of the signal transduced by the antigen receptor may differ, depending on the developmental stage of the responding cell or on the cellular context of antigen recognition. For instance, signal transduction by the TCR in developing thymocytes can lead either to programmed cell death (apoptosis) or to selection, depending on the antigen specificity of the TCR. In mature T cells, TCR recognition of antigen can lead either to differentiation and proliferation or to a long-lived state of unresponsiveness (anergy), depending on whether appropriate second (costimulatory) signals are provided by molecules such as CD28, which interacts with ligands on antigenpresenting cells. This review will focus on the biochemical events induced by the antigen receptors, whereas other reviews in this issue will address the different responses that lymphocytes can make to these signals, depending on developmental and cellular contexts.