Elevated temperature is one of the main stressors with a huge impact on performance in the pig industry, and warming climate will enhance these concerns in the future. Long-term stress lead to acclimation of the pigs to cope with the effect of heat stress (HS) but underlying physiological mechanisms remains poorly described. This study aims to use multi-omics and multi-tissues data to understand the physiological pathways involved in heat tolerance in pigs. Transcriptomic data from seven different tissues (muscle, adipose tissue, liver, blood, pituitary, thyroid, adrenal gland), metabolomics data from four tissues (muscle, liver, plasma, urine), and blood parameters where obtained in an experiment involving 36 pigs from 3 genotypes slaughtered before (n=18) or after a 5-d exposure to 32 °C (n=18). Respiratory rate, rectal and skin temperatures significantly increased within the first 24 to 48 h of exposure to 32 °C when compared to the thermoneutral (TN) conditions (P<0.01). The average daily voluntary feed intake was significantly lower in HS conditions than in TN conditions (1,560 vs 1,707 g/d; P<0.01). With the aim to identify differentially expressed genes (DEG) and differentially produced metabolites, data were analysed with a mixed model with the effects of HS conditions, breed and sire origin. We identified 4,248 DEG in all tissues, with differences in the expression pattern between regulatory tissues (pituitary, thyroid, adrenal gland) and the other tissues. With a pathway enrichment analysis querying KEGG database, we have identified tissue-specific and recurrent pathways. Integrating metabolome with transcriptome data from muscle and sub-cutaneous adipose tissue, we have produced correlation networks about oxidative stress and thermogenesis, two important mechanisms related to HS. Integration of transcriptome data between regulatory tissues and an effector tissue allowed identifying hub genes that could have an importance regarding HS acclimation. This research was part of the MP ACCAF project P10157 (PigChange).