South Africa (SA) has played a leading role in health research internationally. Ethical guidelines for the protection of research participants have been published by the Medical Research Council (MRC) as early as 1979. Ironically, the guidelines gave substantial prominence to the oppressive laws of the time. In its 4th edition of the guidelines, the MRC placed emphasis on SA needs, and incorporated the principles of the Bill of Rights of the SA Constitution 1996 into its guidelines. The most significant milestone in the history of participant protections in SA was the inclusion of research and experimentation in the Bill of Rights of the Constitution and the statutory legislation of protections in the National Health Act No. 61 of 2003.