Poultry provides the largest livestock source of protein for human consumption. Due to this widespread consumption of poultry products, biotic and abiotic stressors of chickens can have negative impacts on the nutrition of humans, as well as the health and productivity of chickens. Salmonella-infected poultry products present a food safety threat to human consumers, while the exposure of poultry to hot environments raises animal welfare issues. Understanding the effects of Salmonella infection and heat stress on immunological and metabolic networks in chickens may help to develop strategies to circumvent these problems. Therefore, gene expression profiles of Salmonella-infected and heat-stressed chickens were characterized. The splenic profiles of selected cytokines in S. Enteritidis-infected broiler, Leghorn and Fayoumi hens were analyzed using Quantitative Polymerase Chain Reaction (qPCR). The results supported the concept that chickens from distinct genetic lines utilize different immune mechanisms in response to S. Enteritidis infection. Systemic metabolic effects were detected in the liver transcriptome of S. Enteritidis-infected broilers using microarrays. A predominant trend of down-regulation was observed among the 44 differentially expressed (DE) genes. Cell Cycle and Metabolism networks were created from Ingenuity Pathway Analysis (IPA) of the DE genes. Metabolic responses were also detected in the liver transcriptome in response to chronic, cyclic heat stress of chickens. Two networks were created from the 40 DE genes, "Cell Signaling, Molecular Transport, Small Molecule Biochemistry" and "Endocrine System Development and Function, Small Molecule Biochemistry Cell Signaling". Members of the Ras-Raf-MEK-ERK (MAPK) signal transduction cascade (MAPK, P38 MAPK, ERK, ERK1/2) were present in the broiler liver transcriptome in response to both S. Enteritidis infection and heat stress, suggesting a common response to a wide range of stressors. This dissertation provides novel insights into the effects of two important stressors, (S. Enteritidis infection and heat stress) on immunological and metabolic-related pathways in chickens, establishing a platform for further investigation into the genomics of the stress response of chickens. Ultimately, understanding the affected immune and metabolic-related pathways may lead to the commercial production of chickens resilient to the effects of S. Enteritidis infection and heat stress.