Poultry products including meat and eggs constitute a major protein source in the American diet and disease-causing pathogens represent major challenges to the poultry industry. More than 95% of pathogens enter the host through the mucosal surfaces of the respiratory, digestive and reproductive tracts and over the past few decades, the two main mechanisms used to control diseases have been the use of vaccines and antibiotics. However, in the poultry industry, there are mounting concerns over the ability of current vaccines to adequately protect against emerging hyper-virulent strains of pathogens and a lack of suitable, cost effective adjuvants. Thorough investigation of the immunogenetic responses involved in host-pathogen interactions will lead to the development of new and effective strategies for improving poultry health, food safety and the economic viability of the US poultry industry. In this paper, I describe the development of immunogenomic and proteomic tools to fundamentally determine and characterize the immunological mechanisms of the avian host to economically significant mucosal pathogens such as Eimeria. Recent completion of poultry genome sequencing and the development of several tissue-specific cDNA libraries in chickens are facilitating the rapid application of functional immunogenomics in the poultry disease research. Furthermore, research involving functional genomics, immunology and bioinformatics is providing novel insights into the processes of disease and immunity to microbial pathogens at mucosal surfaces. In this presentation, a new strategy of global gene expression using avian macrophage (AMM) to characterize the multiple pathways related to the variable immune responses of the host to Eimeria is described. This functional immunogenomics approach will increase current understanding of how mucosal immunity to infectious agents operates, and how it may be enhanced to enable the rational development of new and effective strategies against coccidiosis and other mucosal pathogens.