Drug use research that involves transnational populations in their worksite nations and in their countries of origin requires special consideration for human subjects. These populations are exposed to similar, if not greater, research related risks than other vulnerable research subjects. If they are to be protected adequately, Internal Review Boards (IRBs) need to become familiar with transnational populations and the possible risks that their members face when participating in research that targets their drug use behaviors and practices. Addressed in this article are a number of challenges that IRBs in United States universities and research institutes encounter in assuring protections against possible research risks. Specific areas of concern are: the dearth of binational IRB reviews, IRB inexperience with transnational populations, mandatory written consent, limited research ethics training for researchers, the absence of a vulnerable population research advisory board, and the need for measures in case of a breach of confidentiality. The discourse of each one of these problem areas includes a recommendation for rectifying it. The article ends with five suggested measures that IRBs should consider in protecting transnational migrants from research related risks in the United States and in their homeland. The discussion of human subject problems and of the measures introduced to alleviate them are based on the author's experiences with preparing human subjects protocols for his ethnographic substance abuse research in both the United States and Mexico.