Mastitis is an inflammatory disease of the mammary gland. The disease is generally classified as sub-clinical (no obvious signs) or 3 levels of clinical disease including: mild (abnormal milk); moderate (abnormal milk with swelling or redness of the gland); severe (abnormal milk, gland inflammation, with systemic signs of illness). Recent large-scale studies indicate that mild, moderate, and severe forms make up approximately 60%, 30%, and 10% of clinical cases of mastitis, with severe mastitis predominately caused by gram-negative bacteria. Efforts to reduce severe mastitis are of utmost importance to dairy animal welfare, and these cases are associated with greatest milk production losses. Experimental challenge studies under controlled conditions reveal animal-to-animal variation in the severity of the resulting mastitis. This suggests a genetic basis to disease severity and the potential for finding genetic markers for use in breeding programs to produce animals with a reduced tendency to develop severe mastitis. However, the evolving field of epigenetics suggests that in utero and early life environments can modify gene expression and thus modify an animal’s phenotype. Our approach is to develop a cell culture challenge model predictive of an animal’s innate response phenotype. Such a model could potentially be used with cells from young animals to determine their response phenotype and thus facilitate selection of herd replacements. In our dermal fibroblast model, the cells are cultured under controlled conditions and then challenged with LPS to determine innate response magnitude. This model has revealed breed differences (Angus vs. Holstein) and epigenetic differences in samples from the same animals (i.e., same genotype) collected at 5 and 16 mo of age. Further, animals with low vs. high fibroblast response phenotype produce less BSA in milk following experimentally induced mastitis. Future studies employing this and other model systems, combined with well-controlled disease challenges of extreme phenotypes will lead to a greater understanding of factors contributing to animal variation in the severity of response to mammary infection.