Recent debate has addressed whether global health financing should prioritize interventions that maximize lives saved; focus on the young; and are most economically efficient (most cost-effective). In particular, some have argued that an expansion of the President's Emergency Plan for AIDS Relief (PEPfAR) is not the best use of international health funding, and that extending funding to treat diarrheal and respiratory disease could save more lives at substantially lower costs. We examine the methods of cost-effectiveness analysis and why their application, without context, may not be appropriate for priority setting in this fashion. We further address the substantial impact PEPfAR has achieved in general and more specifically toward improving maternal and child health and why continued PEPfAR investment remains essential.