Harm reduction is both a policy approach and used to describe a specific set of interventions. These interventions aim to reduce the harms associated with drug use. Employing a strict definition of harm reduction, evidence for the efficacy and effectiveness of alcohol, tobacco and illicit drug harm reduction interventions were reviewed. Systematic searches of the published literature were undertaken. Studies were included if they provided evaluation data (pre-post, or control group comparisons). More than 650 articles were included in the review. The majority of the literature concerned illicit drugs. For alcohol, harm reduction interventions to reduce road trauma are well-founded in evidence. Otherwise, there is limited research to support the efficacy and effectiveness of other alcohol harm reduction interventions. For tobacco, the area is controversial but promising new products that reduce the harms associated with smoking are being developed. In the area of illicit drugs there is solid efficacy, effectiveness and economic data to support needle syringe programmes and outreach programmes. There is limited published evidence to date for other harm reduction interventions such as non-injecting routes of administration, brief interventions and emerging positive evidence for supervised injecting facilities. There is sufficient evidence to support the wide-spread adoption of harm reduction interventions and to use harm reduction as an overarching policy approach in relation to illicit drugs. The same cannot be concluded for alcohol or tobacco. Research at a broad policy level is required, especially in light of the failure by many policy makers to adopt cost-effective harm reduction interventions.