Many persons enrolled in clinical trials can be considered vulnerable, and such trials often raise concerns because of the diminished ability of vulnerable persons to consider and protect their own interests. However, this research is necessary to answer important questions, such as which interventions are effective, which have no impact, and which do more harm than good. In this article, we identified six specific challenges associated with randomized clinical trials in vulnerable populations and have suggested several potential solutions to overcome these challenges. First addressed were macro issues, such as the scope of the problem, and research capacity in terms of funding and investigators. Next, we have addressed research ethics review, informed consent, regulatory hurdles, and serious adverse event reporting. As clinical trials are expanding globally, all stakeholders (investigators, granting agencies, REBs, DSMBs, regulatory bodies, universities, hospitals, clinicians, patients, and family members) should be aware of the challenges we have outlined, and work collaboratively toward effective solutions that improve the quality, quantity, safety, and relevance of clinical trials for vulnerable persons around the world.