PLA2 inhibitors specific to Group I and II PLA2 isoforms are therapeutically important as anti-inflammatory molecules and against venom toxicity. From various natural sources diversified molecules with PLA2 inhibition and concomitant neutralization of inflammatory reactions and venom toxicity were characterized. Using these molecules, lead compounds are generated in several laboratories. Analogues of lead molecules were generated by substituting different types of functional groups in order to obtain a molecule with optimal PLA2 inhibition. The lead molecules characterized as PLA2 inhibitors are indoles, azetidinones, piperazines, isoxazolidines, isoxazolines, diazepinones, acenaphthenes and several substrate analogues. The lead optimization involves relative hydrophobicity and substitution of functional groups, such as electron withdrawing or donating. Many such groups are placed on hydrophobic moiety and their positional bioisosters are characterized. Among these analogue piperazine derivatives on optimization with respect to hydrophobicity and electronegativity showed inhibition at nanomolar levels. Structural analysis of many lead molecules indicated that a PLA2 inhibitor should have both hydrophobic moiety and polar functional groups. Each lead molecule requires optimization in this regard for effective inhibition.