Two of the most significant changes in the field of infectious disease management during the last few decades are the emergence of atypical and/or new pathogens that may have devastating consequences and the re-emergence of well-recognised organisms that have acquired antimicrobial resistance through a variety of mechanisms. Erythromycin, the prototype macrolide, was originally marketed approximately five decades ago as a useful alternative agent in the treatment of patients allergic to beta-lactam antibiotics. While clinically useful, its pharmacokinetic and adverse-event profile limited the use of erythromycin to these individuals. Enhancements of the macrolide structure circumvented many of the limitations of erythromycin and resulted in the development of azithromycin and clarithromycin. The clinical uses of clarithromycin and azithromycin are substantially wider than erythromycin due to the wide spectra of activity against the atypical and newer pathogens. In addition, these agents are well-tolerated and have a pharmacokinetic profile that allows once- or twice-daily administration. Studies also indicate that the more common of the two mechanisms of macrolide resistance in the US and Canada imparts only low-level resistance. The multitude of studies substantiating clinical as well as bacteriological success with these two agents indicates that, when used appropriately, they will stand the test of time and continue to be useful antimicrobial agents.