Host defense mechanisms are categorized into different strategies, namely, avoidance, resistance and tolerance. Resistance encompasses mechanisms that directly kill the pathogen while tolerance is mainly concerned with alleviating the harsh consequences of the infection regardless of the pathogen burden. Resistance is well‐known strategy in immunology while tolerance is relatively new. Studies addressed tolerance mainly using mouse models revealing a wide range of interesting tolerance mechanisms. Herein, we aim to emphasize on the interspecies comparative approaches to explore potential new mechanisms of disease tolerance. We will discuss mechanisms of tolerance with focus on those that were revealed using comparative study designs of mammals followed by summarizing the reasons for adopting comparative approaches on disease tolerance studies. Disease tolerance is a relatively new concept in immunology, we believe combining comparative studies with model organism study designs will enhance our understanding to tolerance and unveil new mechanisms of tolerance. Disease tolerance is one of the major immune strategies that recently gained considerable attention in immunology. In this review, we aim to emphasize on the comparative approaches, beside mouse model studies, to uncover potential tolerance mechanisms that results from unique adaptation of animals especially mammals to diverse environments.