Beyond what are characterized as Special Populations in U.S. FDA regulatory considerations is vulnerability of patient populations in a broader context of international guidance. Such a review suggests a rich appreciation for the diversity of patients. Vulnerable patients’ status and the associated patient protections are of growing interest in the clinical research environment. To participate in the current developments and reflections, we selected 12 international & recognized core documents that are discussing human research protections and identify all references to them pertinent to Vulnerables. This allows the identification of 15 different categories of Vulnerability, that we group in five kinds of challenges. We then map significant regulatory and ethical interpretations and their implications toward applying what Vulnerability constitutes for the stakeholder ecosystem and its evolving direction as part of the overall protection for patients, defined as a “chain of protection.” Different levels of understanding are proposed: Who are vulnerable (a ‘macro’-mapping), what is Vulnerability (a ‘meso’-mapping) leading to applications with practical questions (a ‘micro’-mapping). We offer this analysis and mapping for practical benefit to a range of stakeholders with staffs whose functional responsibilities indirectly or directly essentially touch the broad spectrum of involvement with patients. The practical application is for multi-stakeholder consideration of patients-as-subjects in research, especially for Sites and Ethics Committees/IRBs, given the extended efforts of “patient-centricity”—the ‘how’s’ and ‘what’s’ of including patients in the clinical research process from discovery to RWE and its implications. Also considered is the value of education and training purposes on the true diversity of patients so that sensitivity to such matters from protocol development through informed consent and privacy protections are taken into account in the era of “new science,” technological advances, and expansion of clinical research investigators, patient populations, and types of non-traditional research sites.