Since the advent of the antimicrobial era, single-dose therapy has been a valuable tool in the management of genital infection. Most of the common sexually transmitted infections (STIs) such as gonorrhoea, syphilis, trichomoniasis and chancroid can be treated in this way, as can genital infections which are not sexually transmitted such as bacterial vaginosis and genital tract candidiasis. Until recently, treatment for Chlamydia trachomatis infection required a multi-dose regimen, but single-dose azithromycin has now been shown to be an effective and acceptable alternative to this. Unfortunately, eradicative therapy has proven to be elusive for the viral STIs such as genital herpes simplex infection, human papilloma virus infection and human immunodeficiency virus (HIV) infection. The main advantage of single-dose therapy lies in its convenience and in its ability to ensure virtually 100% compliance. This addresses the problems of reduced clinical efficacy and the difficulties in assessing the response to therapy which complicates poor treatment compliance. However, some single-dose regimens for STIs do have drawbacks, particularly in certain situations. This may be with respect to efficacy, for example in syphilis with single-dose benzathine penicillin therapy, particularly for pregnant women and individuals infected with HI. Alternatively, it may involve toxicity, for example with single-dose metronidazole therapy for trichomoniasis or bacterial vaginosis where a higher rate of gastrointestinal adverse effects may be expected than if a lower multi-dose regimen is used. In addition, single-dose therapy, for example with nevirapine, given to the mother in labour and to the baby after delivery significantly reduces the risk of mother to child HIV transmission, but resistance mutations are frequently detected in the viral genome after the brief exposure to the drug, which could jeopardise its future use. Single-dose therapy clearly has both advantages and disadvantages. We have reviewed a range of these in a variety of situations, focussing on their applications, effectiveness, compliance and toxicity, highlighting how single-dose therapy may be a double-edged sword.