Pharmacogenomics (PGx) can personalise medication therapy in South Africa’s (SA) diverse population but faces context-specific barriers: inadequate SA-specific allele variant data, infrastructure limitations, education and training gaps, and economic constraints. This call to action proposes SA’s first PGx stewardship framework to guide rational PGx testing integration. Three critical pillars are as follows (1) targeted research to build an open-access PGx variant database informed by SA data; (2) phased implementation starting with high-risk medicines in tertiary hospitals; and (3) nationally accredited PGx curricula for health professionals. All pillars are grounded in culturally responsive ethical, legal and social frameworks addressing SA’s sociohistorical context. We advocate for interprofessional collaboration to position SA as a leader in equitable PGx implementation, aligning with National Health Insurance priorities to reduce adverse drug reaction (ADR) related hospitalizations by 30% within 5 years.