Nonresolving inflammation is a major driver of disease. Perpetuation of inflammation is an inherent risk because inflammation can damage tissue and necrosis can provoke inflammation. Nonetheless, multiple mechanisms normally ensure resolution. Cells like macrophages switch phenotypes, secreted molecules like reactive oxygen intermediates switch impact from pro- to anti-inflammatory, and additional mediators of resolution arise, including proteins, lipids, and gasses. Aside from persistence of initiating stimuli, nonresolution may result from deficiencies in these mechanisms when an inflammatory response begins either excessively or subnormally. This greatly complicates the development of anti-inflammatory therapies. The problem calls for conceptual, organizational, and statistical innovations.