Globally, Traditional Medicine (TM) plays an important role in healthcare. In South Africa, attempts at regulation of Traditional Health Practitioners (THPs) began in 2007. Implementation efforts include the interim THP Council and proposed regulations. Amidst wide criticism, progress at ground-level is slow. To date, no THPs are registered. The aim of the study was to explore the perspectives of stakeholders on the local realities in relation to the regulation of THPs in order to capitalize on the challenges and opportunities both nationally and internationally. Stakeholders were selected based on a prior stakeholder mapping study to participate in in-depth interviews. The stakeholders belonged to one of the following broad groups: 1) local government, 2) academic experts 3) traditional health practitioner associations or organisations 4) non-government organisations or consumer groups and 5) international organisation or donors. A framework analysis approach was used to arrive at four overarching themes. Perceptions of key challenges and opportunities linked to the implementation of the THP Act are common across stakeholder groups, though with varied explanation. The four overarching themes within which challenges and opportunities were described are: 1) risk-benefit of regulation, 2) understanding, awareness, and paradigmatic opposition, 3) THP-centred research for sustained progress and coexistence, and 4) systemic disadvantage, stigma, and conflict. Global recommendations are clear. However, a more comprehensive understanding of this landscape would lend itself to regulation and policy, truly compatible with the contextual realities. The researchers recommend THP-centred research and capacity-building for implementation and wider health-system benefit.