Abstract The Netherlands is well known for its early adoption of harm reduction (HR) programs at the height of its heroin crisis in the 1970s/1980s, including the implementation of the first needle and syringe program worldwide. In this manuscript, we describe how the Amsterdam Cohort Studies (ACS) among people who use drugs (PWUD) was conceived within the context of the Dutch HR approach, including the challenges scientists faced while establishing this cohort. This required striking a balance between public health and individual benefit, solving research dilemmas in the face of uncertainty, developing controversial innovative and cutting-edge interventions, which changed the prevention landscape for PWUD, and using longitudinal cohort data to provide unique insights. Studies from the ACS covering follow-up between 1985 and 2016 revealed that participation in both opioid agonist therapy and needle and syringe programs led to a major decrease in the risk of HIV and hepatitis B and C infection acquisition. ACS data have shown that the observed decrease in incidence also likely included shifts in drug markets and drug culture over time, selective mortality among those with the highest levels of risk behaviour, demographic changes of the PWUD population, and progression of the HIV and HCV epidemics. Moreover, HR programs in the Netherlands provided services beyond care for drug use, such as social support and welfare services, likely contributing to its success in curbing the HIV and viral hepatitis epidemics, increasing access and retention to HIV and HCV care and ultimately decreases in overdose mortality over time. Given the low coverage of HR programs in certain regions, it is unsurprising that continued HIV and HCV outbreaks occur and that transmission is ongoing in many countries worldwide. If we aim to reach the World Health Organization viral hepatitis and HIV elimination targets in 2030, as well as to improve the life of PWUD beyond infection risk, comprehensive HR programs need to be integrated as a part ...