South Africa has a rich tradition of Indigenous knowledge covering uses of the country’s abundant natural resources. South Africa’s development of a multi-faceted framework for cultural and genetic resource protection in relation to Indigenous knowledge is a promising source of fruitful insights on the challenges and benefits of implementing such protections. As the first in a series of case studies featuring various models of traditional knowledge implementation in domestic legislation, this paper provides an overview of how South Africa is approaching the protection of traditional or Indigenous knowledge. A central aim of this series is to provide objective evidence and insight into national experiences that could serve to inform and support effective policy development in the field, without endorsing any particular national approach.