Penicillin has been widely used for many years for the treatment of yaws and other human treponematoses without the emergence of penicillin-resistant treponemal strains. However, experience with various bacterial pathogens serves to emphasize that resistance to penicillin and other antibiotics can suddenly appear after decades of exquisite sensitivity. The finding of plasmid DNA in at least one strain of Treponema pallidum, the reporting of several instances in which antibiotic treatment of syphilis has failed, and the demonstration that a recent clinical isolate of T. pallidum is resistant to erythromycin indicate that the pathogenic treponemes do have the potential to develop antibiotic resistance. Although it is impossible to predict when antibiotic resistance might become a significant problem in dealing with infections caused by these organisms, the vigorous pursuit of alternatives to antibiotic therapy for the control of human treponematoses seems prudent.