BACKGROUND: People who experience homelessness and those vulnerably housed experience disproportionately high rates of drug use and associated harms, yet barriers to services and support are common. We undertook a systematic 'review of reviews' to investigate the effects of interventions for this population on substance use, housing, and related outcomes, as well as on treatment engagement, retention and successful completion.

METHODS AND FINDINGS: Our search identified 843 citations, and 25 reviews met the inclusion criteria. Regarding substance use outcomes, there was evidence that harm reduction approaches lead to decreases in drug-related risk behaviour and fatal overdoses, and reduce mortality, morbidity, and substance use. Case management interventions were significantly better than treatment as usual in reducing substance use among people who are homeless. The evidence indicates that Housing First does not lead to significant changes in substance use. Evidence regarding housing and other outcomes is mixed.

CONCLUSIONS: People who are homeless and use drugs experience many barriers to accessing healthcare and treatment. Evidence regarding interventions designed specifically for this population is limited, but harm reduction and case management approaches can lead to improvements in substance use outcomes, whilst some housing interventions improve housing outcomes and may provide more stability. More research is needed regarding optimal treatment length as well as qualitative insights from people experiencing or at risk of homelessness.