Macrolides and tetracyclines are the most active antibiotics against mycoplasmas in vitro. In particular, erythromycin has been widely used for the treatment of infections caused by Mycoplasma pneumoniae. However, improvements in therapy are needed to accommodate specific characteristics of the microorganism or unusual manifestations of the illness it causes. Because no rapid microbiological technique is available for the diagnosis of M. pneumoniae infections, empirical treatment must be effective against other relevant pathogens as well. Macrolides and fluoroquinolones have recently undergone substantial development. The newer macrolides have more favorable pharmacokinetic properties and are better tolerated than older agents of this class, while the newer fluoroquinolones exhibit a broadened spectrum of in vitro activity that in some instances includes M. pneumoniae and Streptococcus pneumoniae. Although the existing data on in vivo efficacy are only preliminary, the newer macrolides and fluoroquinolones are promising agents for the treatment of M. pneumoniae infection and, more generally, for that of community-acquired pneumonia.