Globally, many nations are legislating access for bioprospecting purposes to their biological and genetic resources. South Africa, as a megadiverse country, has recently regulated bioprospecting, access and benefit-sharing activities in accordance with its obligations as a ratifying party to the Convention on Biological Diversity. The context and process of key legislation developments in South Africa are discussed, prior to our presenting a critique which emphasizes the practical impacts, especially on drug discovery, arising from the newly introduced systems. Probable effects on existing bioresource-based industries within South Africa, together with current as well as future bioprospecting activities, are assessed. Several practicalities of bioprospecting methods have been poorly accommodated, resulting in the development of impracticable and unnecessarily restrictive regulations. We conclude that though well-intentioned, these non-facilitative regulations have placed a dead hand on value-addition to South Africa's biodiversity. Bioprospectors will find it difficult to continue with broad-scale screening programmes given their user insecurity, legal uncertainty, and cost-inefficiency. Existing bioresource-based industries within South Africa face potential closure in view of onerous bioprospecting permit application requirements. An alternative, practical, CBD-compliant model on which to base urgently required legislative reforms is presented.