Testing the safety and efficacy of a successful human medicine involves many laboratory animals, which can sometimes be subjected to considerable suffering and distress. Also, it is necessary to extrapolate from the test species to humans. UK and European legislation requires that Replacement, Reduction and Refinement of animal procedures (the Three Rs) are implemented wherever possible. Over the last decade, there has been substantial progress with applying in vitro and in silico methods to both drug efficacy and safety testing. This paper is a report of the discussions and recommendations arising from a workshop oh the role that might be played,by human volunteer studies in the very early stages of drug development. The workshop was organised in November, 2001 by Volunteers in Research and Testing, a group of individuals in the UK which launched an initiative in 1994 to identify where and how human volunteers can participate safely in biomedical studies to replace laboratory animals. It was considered that conducting pre-Phase I very low dose human studies (sub-toxic and below the dose threshold for measurable pharmacological or clinical activity) could enable drug candidates to be assessed earli