Chlamydia (C.) trachomatis is the most common bacterial cause of sexually transmitted disease in the world. A well documented feature of chlamydial infection is its high rate of recurrence among sexually active populations. However, it is difficult to distinguish whether the high rate of recurrent disease is due to reinfection or to persistent infection with the same organism. Of particular concern in this era of increasing antibiotic resistance is whether persistent infection is the consequence of increasing resistance to standard antimicrobial therapy. Azithromycin and doxycycline are considered by the Centers for Disease Control and Prevention (CDC) as first line drugs for the treatment of chlamydial infections; erythromycin, ofloxacin and levofloxacin are recommended as alternative-regimen. Although C. trachomatis has been historically sensitive to these antibiotics, in vitro resistance is being increasingly reported. However, although in vitro antimicrobial resistance has been described, the clinical significance of these findings is unknown. C. pneumoniae is associated with community-acquired pneumonias, acute exacerbations of chronic bronchitis, otitis media, sinusitis and reactive airway disease. Persistent nasopharyngeal infection with C. pneumoniae has been documented in adults following acute respiratory infection. Chronic infection with C. pneumoniae has also been implicated in the pathogenesis of atherosclerosis, although this is still very controversial. Azithromycin, clarithromycin and quinolones are frequently used for the treatment of C. pneumoniae respiratory infections. Microbiologic failure has been described in C. pneumoniae infections, even after prolonged courses of azithromycin, erythromycin and doxycycline.