Recent studies have revealed a distinct class of bacterial effectors defined by the presence of EPIYA or EPIYA-related motif. These bacterial EPIYA effectors are delivered into host cells via type III or IV secretion, where they undergo tyrosine phosphorylation at the EPIYA motif and thereby manipulate host signalling by promiscuously interacting with multiple SH2 domain-containing proteins. Up to now, nine EPIYA effectors have been identified from various bacteria. These effectors do not share sequence homology outside the EPIYA motif, arguing against the idea that they have common ancestors. A search of mammalian proteomes revealed the presence of a mammalian EPIYA-containing protein, Pragmin, which potentiates Src family kinase (SFK) activity by binding and sequestrating the SFK inhibitor Csk upon EPIYA phosphorylation. As several bacterial EPIYA effectors also target Csk, they may have evolved through generation of sequences that mimic the Pragmin EPIYA motif. EPIYA motifs are often diverged through multiple duplications in each bacterial effector. Such a structural plasticity appears to be due to intrinsic disorder of the EPIYA-containing region, which enables the bacterial effectors to undergo efficient phosphorylation and mediate promiscuous interaction with multiple host proteins. Given the functional versatility of the EPIYA motif, many more bacterial EPIYA effectors will soon be emerging.