To paraphrase Anna Karenina, whereas all inactive SFKs are alike, active kinases can be active in different ways. Fully active, fully disassembled SFKs (Fig. 1B) are characterized by: (i) disruption of intra-molecular interactions in which both the SH3 and SH2 domains participate, (ii) the presence of a phosphotyrosine (pY) residue within the activation loop of the kinase domain (which arises as a consequence of autophosphorylation), and (iii) the presence of an unphosphorylated Y residue within the C-terminal tail of the enzyme [2,3]. However, SFKs need not be fully disassembled to be active. Thus, dissociation of the SH3 domain from its inhibitory intra-molecular interactions is alone sufficient to activate an SFK. Such dissociation can be driven by artificial or naturally occurring mutations, within either the SH3 domain, the SH2-kinase linker, or the kinase domain [2,3]. In addition, because the proline-rich sequence in the SH2-kinase linker (PX4PX12P) binds to the SH3 domain with low affinity, it can be displaced by inter-molecular interaction of the SH3 domain with higher affinity proline-rich sequences (e.g., PXXPXR) in other proteins (Fig. 1C) [2,3]. Interestingly, SFKs that are activated by disruption of their SH3 domain-dependent intra-molecular interactions may retain the intra-molecular interaction between the C-terminal pY residue and the SH2 domain, because the latter interaction is required for inhibition, but need not be disrupted for activation, of the SFK . Dissociation of the SH2 domain from its intra-molecular interaction with the inhibitory C-terminal pY residue, which is accompanied by dissociation of the SH3 domain from its intra-molecular interactions , is also sufficient to activate SFKs (Fig. 1D). Although such dissociation has been artificially driven by substitution of the C-terminal Y residue with phenylalanine  or by elimination of the C-terminal tail of the enzyme altogether , this interaction can be disrupted upon dephosphorylation of the C-terminal pY residue [Fig. 1D(i)], which can be accomplished by a number of different phosphatases, including proline-enriched tyrosine phosphatase (PEP), T-cell protein tyrosine phosphatase (TCPTP), tandem SH2 domain-containing protein tyrosine phosphatase-1 (SHP-1), and CD45 . In addition, as is the case with the SH3 domain, the pY-containing sequence in the C-terminal tail (pYQPG, pYQQQ, or pYQPQ) binds to the SH2 domain with relatively low affinity, and can be easily overcome by pY-containing sequences (e.g. pYEEI) in other proteins for which the SH2 domain has higher affinity [Fig. 1D(ii)] [2,3]. In this latter case, the active SFK may, but need not, be dephosphorylated on its C-terminal Y residue .