Several lichen metabolites, such as usnic acid, inhibit both HIV-1 and HIV-2 integrase activities, as well as mammalian topoisomerase I. Some of them are phenolics, which also inhibit leukotriene B4 biosynthesis in polymorphonuclear leukocytes. Their effect is not due to an antioxidant effect against peroxidation , free radical scavenging or free radicals production. (-)-Usnic acid specifically bleaches the cotyledonary tissues and decreases chlorophylls and carotenoids; it also inhibits protophorphyrinogen oxidase activity. Bleaching appears to be caused by the competitive binding of (-)-usnic acid, inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase. (-)-Usnic acid also promotes the secretion of active bacterial glucosamine phosphate isomerase and lactate dehydrogenase. Usnic acids are able to bind several enzymatic and non-enzymatic proteins, for example urease, which is inhibited by the formation of large inactive aggregates. L-Cysteine partially reverses urease inhibition by binding to usnic acid via their thiol groups, thus preventing its effect on the enzyme. Consistent with this, reducing reagents such as DTT also relieve urease inhibition by usnic acid. In addition, alanine and proline partially reverse urease inhibition and formation of large aggregates. These amino acids also prevent the binding of (-)-usnic acid to the low affinity sites for the ligand. The involvement of proline in the polymerization process is related to the biplanar, steric conformation of (-)-usnic acid. Other lichen phenolics, such as evernic acid, possessing a monoplanar structure, also inhibit the enzyme without polymerization, by interaction with the L-histidine and L-serine residues. This review focuses on the mechanisms of urease inhibition by these metabolites and their regulation, postulating a mechanism of action for these inhibitors related to their potential applications in drug development.