The development of ethical guidelines and regulations regarding human subjects research has focused upon protection of vulnerable populations by relying on a categorical approach to vulnerability. This results in several challenges: First, Institutional Review Boards (IRBs) struggle to interpret and apply the regulations because they are often vague and inconsistent. Second, applying the regulations to subjects who fit within multiple categories of vulnerability can lead to contradictions and the rejection of research that would be permissible if only one category were applicable. Finally, some potential subjects have social and other context-based vulnerabilities that are not described in the federal regulations and therefore not considered in IRB deliberations. IRBs and investigators lack guidance on how to address the problem of multiple vulnerabilities in a way that strikes a balance between protection and respect for persons. In this essay, we evaluate the acceptability of the existing federal regulations with respect to research participants with multiple vulnerabilities, offer strategies for rethinking the concept of vulnerability, and outline a context-based normative framework to account for the compounding effects of multiple vulnerabilities.