Plant extracts with a high content of proteolytic enzymes have been used in traditional medicine for a long time. Besides herbal proteinases, 'modern' enzyme therapy includes pancreatic enzymes. The therapeutic use of proteolytic enzymes is empirically based, but is also supported by scientific studies. This review provides an overview of preclinical and clinical trials of systemic enzyme therapy in rheumatic disorders. Studies of the use of proteolytic enzymes in rheumatic disorders have mostly been carried out on enzyme preparations consisting of combinations of bromelain, papain, trypsin and chymotrypsin. The precise mechanism of action of systemic enzyme therapy remains unresolved. The ratio of proteinases to antiproteinases, which is affected by rheumatic diseases, appears to be influenced by the oral administration of proteolytic enzymes, probably via induction of the synthesis of antiproteinases or a signal transduction of the proteinase-antiproteinase complex via specific receptors. Furthermore, there are numerous alterations of cytokine composition during therapy with orally administered enzymes resulting from immunomodulatory effects, which might be an indication of the efficacy of enzyme therapy. The results of various studies (placebo-controlled and comparisons with nonsteroidal anti-inflammatory drugs) in patients with rheumatic diseases suggest that oral therapy with proteolytic enzymes produces certain analgesic and anti-inflammatory effects. However, the results are often inconsistent. Nevertheless, in the light of preclinical and experimental data as well as therapeutic experience, the application of enzyme therapy seems plausible in carefully chosen patients with rheumatic disorders.