Due to the threat of vaccination problems and antibiotic resistance, more appropriate approaches are desired to breed disease resistance animals that are now practiced in cattle, sheep, chicken, and fish farming. Over the recent century, breeding programs based on the productive characteristics have increased animals' overall growth rate and produc-tivity. Despite the benefits, livestock breeding with this method has caused many physiological disorders as well as a reduction in overall immunocompetence. This issue highlights the importance of genetic considerations during the process of breeding. One of the most crucial gene clusters identified in animals is the major histocompatibility complex (MHC), which plays a crucial role in the immune system to distinguishing self from non-self. Recent studies have demonstrated that some MHC regions are highly polymorphic. Also, a significant association between different MHC alleles and susceptibility/ resistance to various diseases has been found. This review summarizes the recent research on MHC polymorphism and its association with immune responses in domestic animals