The paper reviews the main findings from substance misuse research carried out over the last two decades in South America looking at the main initiatives aimed at reducing drug related harm and curbing the spread of HIV/AIDS and other sexually transmitted and blood-borne diseases. The current challenges faced by harm reduction in the region are analysed from the perspective of the history of coca and its different uses in South America. Except in Brazil and Argentina, the implementation of initiatives to reduce drug related harm in South America has been very cautious. The paper aims to link the analysis of harms associated with the use of illicit substances, with the often paradoxically harmful effects of supply-side drug policies in the world’s largest coca/cocaine producing area. Despite the undeniable success of many initiatives, the broader context of harm maximization through structural violence and entrenched corruption acts as a major disincentive for the comprehensive adoption of sound public health policies.