The article discusses the concept of disease tolerance as a distinct host defense strategy, which has been largely overlooked in animal and human studies. Disease tolerance refers to the ability of a host to reduce the negative impact of an infection on its fitness without directly affecting the pathogen burden. The authors argue that this strategy should be integrated into the conceptual toolkit of immunology to expand our understanding of infectious diseases and host-pathogen interactions. They highlight three main strategies for protecting against infectious diseases: avoidance, resistance, and tolerance. Avoidance involves altering host behavior to reduce the risk of exposure to pathogens, resistance involves reducing the pathogen burden once infection is established, and tolerance reduces the negative impact of an infection on host fitness. The article provides examples of tolerance mechanisms in various organisms, such as plants, animals, and humans, and discusses the potential therapeutic applications of understanding and enhancing tolerance mechanisms. The authors also explore the relationship between tolerance and other aspects of host defense, such as sickness behavior and immunodeficiencies, and suggest that tolerance may play a crucial role in the severity of infectious diseases across different ages. Finally, they emphasize the importance of characterizing tolerance mechanisms to develop effective treatments for infectious, inflammatory, and autoimmune diseases.The article discusses the concept of disease tolerance as a distinct host defense strategy, which has been largely overlooked in animal and human studies. Disease tolerance refers to the ability of a host to reduce the negative impact of an infection on its fitness without directly affecting the pathogen burden. The authors argue that this strategy should be integrated into the conceptual toolkit of immunology to expand our understanding of infectious diseases and host-pathogen interactions. They highlight three main strategies for protecting against infectious diseases: avoidance, resistance, and tolerance. Avoidance involves altering host behavior to reduce the risk of exposure to pathogens, resistance involves reducing the pathogen burden once infection is established, and tolerance reduces the negative impact of an infection on host fitness. The article provides examples of tolerance mechanisms in various organisms, such as plants, animals, and humans, and discusses the potential therapeutic applications of understanding and enhancing tolerance mechanisms. The authors also explore the relationship between tolerance and other aspects of host defense, such as sickness behavior and immunodeficiencies, and suggest that tolerance may play a crucial role in the severity of infectious diseases across different ages. Finally, they emphasize the importance of characterizing tolerance mechanisms to develop effective treatments for infectious, inflammatory, and autoimmune diseases.