S eldom in the evolution of a scientific subdiscipline does one witness such rapid progress and coalescence of thought as has occurred recently in the A@ c receptor signal transduction field. During the past 5 years, this field has evolved from a state in which the principals could do little more than bemoan the perceived unfathomable complexity of the paradigm to one in which the molecular players and their mode of regulation are to a significant extent elucidated. The impact of this progress lies hot only at the level of intellectual satisfaction but also in the newfound targets for discovery of drugs that may one day improve the human condition. As with all such revolutions, the enormous progress in this field had its catalyst. And, as is so often the case, the catalytic event was not immediately recognized as such, and in fact its significance was widely questioned. The catalytic event was not a seminal experiment, but rather a product of keyboard science. It was the recognition in 1989 by Michael Reth (I) that many of the component chains of Ag and Ig Fc receptors contain a common sequence motif in their cytoplasmic tails (Fig. I). The motif, which has come to be known as the immunoreceptor tyrosine-based activation motif (ITAM)’(2), consists of six conserved amino acid residues spaced precisely over an-26-amino acid sequence (D/EX, D/EX, YX, LX, YX, L). Its predominant occurrence in receptor chains that were thought to be involved in signal transduction rather than extracellular ligand binding, and its location in cytoplasmic tails, suggested a role in interaction with cytoplasmic signaling effectors. Interestingly, the motif is found in certain viral proteins, including bovine leukemia virus gp30 and EBV proteins LMP2A and EBNA2, raising suspicion that these molecules could provide a signaling function in viral pathology. The suggestion that this motif might serve a specific function was met with skepticism, mostly because so few residues are conserved over a significant length of