Ketolides are new medicinal chemical entities. They are obtained by removing the 3-L-cladinose sugar moiety from erythronolide A and oxidation of the resulting 3-hydroxyl. They were designed to overcome erythromycin A resistance within Gram-positive cocci. The 3-keto group is responsible for the lack of induction of macrolide resistance, high stability in acidic environments, and the ability to overcome resistance due to methylation of 23SrRNA. The C11-C12 carbamate ketolides are able to overcome efflux and hydrolysis mechanisms of resistance and possess additional mechanisms of action at the ribosome level in comparison with erythromycin A. The nature of the side-chain substituting the C11-C12 carbamate residue is responsible for enhancing the in vitro and in vivo activities in comparison with clarithromycin, for the pharmacodynamic and pharmacokinetic properties, for the intracellular features, and for tolerance. This C11-C12 side-chain is supporting the development of new ketolides.