Substance abuse in South Africa is highly prevalent and continues to be a major cause of mortality and a risk factor for both communicable and non-communicable diseases. The employer costs associated with substance abuse remain high owing to rising health costs, accidents, absenteeism, and workers’ compensation claims placing the organisation and its employees at risk for harm. This article describes the status of current policy, prevention, and treatment interventions to address substance abuse in the South African workplace. Key issues highlighted are the need for research into the extent and impact of substance abuse in the South African workforce, the promotion of substance abuse policies that are comprehensive in nature, and the need to upscale prevention and treatment initiatives through a move away from a traditional labour approach to addressing substance-related disorders in the workplace to the adoption of a more public health approach. Cost-effectiveness of substance abuse interventions is explored alongside the importance of ensuring that employers, practitioners, and other role players engage with the evidence of what works using international standards as the basis.