In the 1890s, hyperimmune sera proved effective in animals against challenge by the snake venom against which they had been raised. They were first used, apparently successfully, in a human patient in about 1895. Since then, antivenoms have become accepted as the only reliable specific treatment for snake-bite envenoming. Despite decades of accumulated clinical experience and a number of published randomized comparative and observational studies, the clinical effectiveness and safety of some antivenoms remain open to question, due to a lack of robust randomized controlled trial data.Antivenoms in some poorly regulated markets may have high rates of potentially fatal adverse effects and their use must be balanced by demonstrable effectiveness. Even those manufactured to strict regulatory requirements may pose a rare risk of severe adverse reactions.Most antivenoms currently marketed around the world were registered without first being studied clinically. There is increasing pressure to subject antivenoms, even those that are long-established, to the same protocols of rigorous pre-clinical and clinical assessment that are standard regulatory requirements for other drugs. Conventional clinical testing progresses through Phases I, II, III to IV. Most authorities consider antivenoms too dangerous to be used in Phase I studies in healthy volunteers. An alternative method for preliminary estimation of safety, dose-finding and effectiveness, is proposed - the “3 + 3” dose escalation or de-escalation design, in volunteer patients, as used in oncology to test cytotoxic drugs.Antivenoms are so widely used and well trusted, that there are few ethical justifications for placebo controls. However, placebo might be ethically justified if there were no proven effective treatment and or if withholding or delaying treatment posed acceptably negligible risks to the participants.Antivenom trials are most urgently needed in low-to middle-income countries where there are many practical, logistical and funding challenges. Basic requirements for clinical trials include identification of the biting species of snake in every case; the use of objective, clinically-relevant endpoints, such as restoration of blood coagulability; definition of inclusion, exclusion and withdrawal criteria; assurance of antivenom safety; ethical considerations; inclusion of one or more control (comparator) groups; and analysis based on intention to treat. The highest quality evidence comes from Phase II and larger Phase III studies that have been designed as statistically powerful, randomized, controlled trials (RCTs), ideally with blinding of patients and investigators to avoid bias. Because of the challenges to carrying out clinical trials of antivenoms, Phase IV trials (post-marketing surveillance) are potentially more important and useful than for most other drugs.