The Src family of tyrosine protein kinases consists of nine related proteins (Src, Yes, Lyn, Fyn, Lck, Blk, Fgr, Hck, and Yrk) that participate in cellular transformation and intracellular signal transduction. In addition to the C-terminal tyrosine kinase domain (SHl), Src family members share conserved internal homology regions, denoted SH2 and SH3 (Figure 1). The N-terminal region is primarily responsible for targeting the Src-related proteins to cellular membranes, particularly the inner surface of the plasma membrane. Unlike transmembrane proteins, which contain stretches of hydrophobic amino acids, membrane targeting of Src-related proteins is mediated by distinct coand posttranslational modifications that occur within the N-terminal domain. Recent findings have shed light on the novel mechanisms utilized by the Src family, as well as other proteins, to facilitate membrane binding. N-Terminal Myristylation: Not Just Fat All Src family members, as well as nearly 100 other viral and cellular proteins, contain a consensus sequence for attachment of the 14 carbon saturated fatty acid, myristate: Met-Gly-XXX-Ser/Thr (Figure 1). During translation, the initiator methionine residue is removed by methionine aminopeptidase. Covalent linkage of myristate via amide bond to the N-terminal glycine also occurs cotranslationally, in a reaction catalyzed by the soluble enzyme N-myristyl transferase. N-myristylation is a “permanent” modification; the half-life of the acyl chain moiety is equivalent to that of the polypeptide backbone.