In cattle, genetic variation exists in regulation of body temperature and stabilization of cellular function during heat stress. There are opportunities to reduce the impact of heat stress on cattle production by identifying the causative mutations responsible for genetic variation in thermotolerance and transferring specific alleles that confer thermotolerance to breeds not adapted to hot climates. An example of a mutation conferring superior ability to regulate body temperature is the group of frame-sift mutations in the prolactin receptor gene (PRLR) that lead to a truncated receptor and development of cattle with a short, sleek hair coat. Slick mutations in PRLR have been found in several extant breeds derived from criollo cattle. The slick mutation in Senepol cattle has been introgressed into dairy cattle in Puerto Rico, Florida and New Zealand. An example of a mutation that confers cellular protection against elevated body temperature is a deletion mutation in the promoter region of a heat shock protein 70 gene called HSPA1L. Inheritance of the mutation results in amplification of the transcriptional response of HSPA1L to heat shock and increased cell survival. The case of PRLR provides a promising example of the efficacy of the genetic approach outlined in this paper. Identification of other mutations conferring thermotolerance at the whole-animal or cellular level will lead to additional opportunities for using genetic solutions to reduce the impact of heat stress. •Genetic variation exists in regulation of body temperature and stabilization of cellular function during heat stress.•There are opportunities to reduce the impact of heat stress on cattle production by transferring specific alleles that confer thermotolerance to breeds not adapted to hot climates.•One successful example of this approach is introgression of the slick mutation in PRLR from Senepol to dairy cattle.