Abstract Climatic variables can trigger physiological, biochemical, hematological, and hormonal alterations that influence the maintenance of homeothermy and can affect production and productivity in cattle. An understanding of pathways leading to resistance/tolerance in cattle is necessary, so that the impact of these changes can be mitigated. Particularly, heat stress (HS) has complex effects on the physiology and genetics of production characteristics in animals, thereby making the use of genomic information to select thermotolerant animals difficult. This review looks at physical, physiological, molecular, and genetic aspects of heat tolerance in cattle and the interrelationship between them.