The research literature on screening and brief intervention (SBI) for unhealthy alcohol use is large and diverse. More than 50 clinical trials and 9 systematic reviews have been published on SBI in a range of healthcare settings, and via a variety of delivery approaches, in general practice, hospital wards, emergency departments, addiction treatment centres, and more recently, via computers and the Internet. The aim of this paper was to discuss methodological issues which arise in the design, analysis, interpretation, and reporting of SBI trials. Principal among these are the challenge of detecting small effects, standards of analysis, reporting, and interpretation, the risks of bias arising from self-report of outcomes, and the need to ensure that results have the potential to be applied in practice to reduce the burden of disease and injury attributable to unhealthy alcohol use.