Heat stress (HS) undermines production efficiency in all animal agriculture, culminating in major economic losses annually. The effects of HS in pigs is realized through depressed growth, altered body composition, and impaired reproductive performance. Pigs, unlike other mammals, do not possess functional sweat glands, making them rely on other mechanisms to thermoregulate during a heat challenge. Continual investigation of hyperthermia in pigs is crucial for developing new strategies and/or technologies that mitigate the effects of HS imposed on the pork industry. The studies conducted in this dissertation investigate the complex interplay of whole-animal physiology as well as cellular and molecular mechanisms within specific tissues. Identifying pigs demonstrating HS tolerance without compromising productivity would be valuable. Thus, study 1 (chapter 2) was carried out to evaluate the degree to which thermoregulatory responses are associated with production phenotypes during acute HS. Hyperthermic pigs accumulate more adipose tissue than their feed intake predicts, which may be mediated by HS-induced hyperinsulinemia. However, less is known how HS influences fatty acid composition and adipocyte size, both of which are regulated by insulin and can influence carcass fat quality. To better understand the underlying physiology of how HS influences body composition, study 2 (chapter 3) investigated insulin’s potential role in affecting adipose characteristics during HS. A cardinal physiological response to HS is compromised intestinal integrity and concomitant increased gut-derived lipopolysaccharide (LPS) into systemic circulation. While HS causes female infertility, many of the reproductive consequences imposed by the abiotic factor are also recapitulated by direct exposures to LPS independently. Additionally, heat shock proteins are known as molecular stress responders, but their roles during in vivo periods of stress in the ovary are ill-defined. Thus, study 3 (chapter 4) was conducted to evaluate the direct and indirect (i.e., LPS) effects of HS on ovarian heat shock protein machinery. Recent studies also demonstrate that body composition and metabolic responses to HS can also be programmed via gestational HS, directly impacting the progeny’s postnatal development. Developmental programming is mediated through specific epigenetic mechanisms and study 4 (chapter 5) investigated alterations to DNA methylation and protein responses in muscle as a result of intrauterine HS. In conclusion, the cumulative discoveries within this dissertation expands our knowledge regarding the negative consequences of thermal biology in pigs, a pivotal step for mitigating the deleterious effects of environmental HS on animal health and performance.