Acne is a common and disfiguring disease affecting a significant proportion of the general population. In milder cases topical therapy is sufficient. However, in more severe cases where papulopustular or nodulocystic acne is present, there is a need of systemic treatment. The latter include antibiotics, anti-androgens and retinoids. A systematic review of the literature was performed of systemic monotherapy using these drugs. Because of the significant methodological variability of the studies examined, it was not possible to make a meta-analysis. Instead the overall effects were assessed by calculating mean weighted effects across different reported effect variables. Isotretinoin scored 85 ± 10% improvement compared with the baseline, whereas tetracyclines and cyproterone acetate plus ethinyloestradiol were less effective (54 ± 3% versus 65 ± 4% improvement compared with baseline, respectively). Moreover, studies suggested that isotretinoin reduces the risk of acne relapse in the few studies that included a follow-up period. A number of restrictions limit the general use of these drugs as monotherapy, e.g., potential teratogenicity. There is a continued need for effective drugs for the therapy of acne, although judicious combined use of existing topical and systemic therapies offers great relief to many patients. In addition, methodological problems in previous studies prevent adequate synthesis of existing knowledge within the framework of evidence-based medicine. There is therefore a demand for future standardisation of further acne studies to enable direct comparison of different treatment efficacies.