The practice of priority-setting in global health has evolved to include both helpful strengths and extraordinary weaknesses. This chapter explores how context and methods shape the priority-setting process and influence its outcomes through an historical analysis of four cases of decision-making about cholera and diarrheal diseases: in Jamaica in 1850, in London in 1866, by multilateral development agencies in the 1980s, and by Gavi, the Vaccine Alliance in 2006. The chapter focuses on the nature of the state–citizen relationship, the type of evidence used, the methods of analysis employed, and the identity of those whose judgment is applied to explain variation in decision-making. Analyzing these examples suggests that priority-setting has evolved to become a narrow exercise incapable of reckoning broader problems, ill suited to assessing comprehensive solutions, and unlikely to contribute to the development of state capacity. Taken together, these findings argue for rethinking priority-setting methods to better account for a wider range of problems, more participatory processes, and more comprehensive solutions.