In the field of traumatic stress, chemoprophylaxis is a term that is often used but rarely well understood. There has been no shortage of debate on the issue, but few rigorous studies to ground the discussion. The purpose of the current paper is to explore the issues surrounding this contentious area. Databases including PubMed, PsychArticles and Web of Knowledge were searched using the key words 'chemo or pharmaco', 'prevention or prophylaxis', and 'PTSD or post-traumatic stress'. Relevant journals and reference lists of the papers obtained through this search were scanned for additional references. Studies that investigated the use of pharmacotherapy to prevent the onset of post-traumatic stress disorder were considered for this paper. Studies that examined the treatment of established PTSD were excluded. A total of 15 empirical studies were included in the review (including five randomized controlled trials), and twice as many non-data-driven papers. Evidence for the prophylactic use of alcohol, morphine, propranolol, and hydrocortisone is presented, followed by a discussion of the many challenges of using pharmacological interventions in this context. While attention to this issue has increased in recent times, the dearth of empirical data has done little to further the field. Larger studies are indicated following small trials with medications such as propranolol and hydrocortisone. There remain a number of ethical and practical questions to be answered before the widespread use of chemoprophylaxis can be recommended.