Phospholipases A2 (PLA2s) are important constituents of snake venom (SV) and are characterized by a high-conserved primary, secondary and tertiary structures throughout the phylogeny, from basal metazoa to mammalian (M). However, compared to the M-PLA2s homologues, they possess many pharmacological and toxic properties, ranging from the inhibition of coagulation to the blockage of nerve transmission, and the induction of muscle necrosis. Increasing studies demonstrated that both SV-PLA2s and the homologues M-PLA2s possess other functions in addition to their well-known phospholipase activity. A demonstration of such finding is that some SV-PLA2s are naturally devoid of enzymatic activity but have the same toxicity of the catalytically active homologous proteins. Here researchers distinguished SV-PLA2s from their homologues secretory M-PLA2s thanks to their structures and biological activity and compared their primary sequences to unveil structural differences that can justify their divergent behavior. Thanks to this bioinformatical analysis, researchers identified three peculiar regions (two in the central part and one in the C-terminal) able to discriminate PLA2s categories. Moreover, herein researchers identified short amino acid stretches known to participate in protein–protein interactions processes, named short linear motifs (SLiMs), specific of M-PLA2s and not present in SV-PLA2s, or vice versa. Here researchers suggest that the biological activity of SV-PLA2s may be regulated by the presence of SLiMs that mediate the interaction with specific membrane or adaptor proteins with which form toxic complexes, or by the absence of other motifs necessary for the interaction with inhibitor proteins able to block the toxic activity of PLA2s.