The World Health Organization's (WHO's) leadership challenges can be traced to its first decades of existence. Central to its governance and practice is regionalization: the division of its member countries into regions, each representing 1 geographical or cultural area. The particular composition of each region has varied over time-reflecting political divisions and especially decolonization. Currently, the 194 member countries belong to 6 regions: the Americas (35 countries), Europe (53 countries), the Eastern Mediterranean (21 countries), South-East Asia (11 countries), the Western Pacific (27 countries), and Africa (47 countries). The regions have considerable autonomy with their own leadership, budget, and priorities. This regional organization has been controversial since its beginnings in the first days of WHO, when representatives of the European countries believed that each country should have a direct relationship with the headquarters in Geneva, Switzerland, whereas others (especially the United States) argued in favor of the regionalization plan. Over time, regional directors have inevitably challenged the WHO directors-general over their degree of autonomy, responsibilities and duties, budgets, and national composition; similar tensions have occurred within regions. This article traces the historical roots of these challenges.