Submitted in fulfilment of the degree of Doctor of Philosophy (PhD) in Bioethics and Health Law, Steve Biko Centre for Bioethics, University of the Witwatersrand. Johannesburg, November 2014 / Vulnerability, an abstract concept in health research, has concrete effects both on those who are labelled vulnerable and those who are not. It has been used increasingly as an exclusion criterion in research but has been the least examined from an ethical perspective despite being linked in most research ethics guidelines and codes, both international and local, to questions of justice and informed consent. Neither has there been an agreed upon standard for identifying and responding to vulnerability. The guidelines, despite categorizing vulnerable research participants into groups and subpopulations, do not offer a robust and comprehensive definition of vulnerability. The study aimed to analyse the notion of vulnerability in health research with a view to constructing an operational definition of the concept which would assist researchers and RECs to identify and understand vulnerabilities and strategize on maximizing protections for the participants without obstructing essential research. Using normative, metaethical and historical methods of bioethical inquiry, this research has shown that the categorization of people into vulnerable groups is not justified as it could result in obstructing research, and paternalistically excluding participants from necessary research, or inadequately protecting participants enrolled in research. The study has resulted in an appropriate operational definition of vulnerability and a Vulnerability Assessment Scale being developed to assist Research Ethics Committees and researchers identify participants with vulnerabilities and develop focused safeguards for their protections. The concept of vulnerability in health research is no longer nebulous and vague and its definition is therefore no longer an unanswered question.