The biggest challenge for host immune defense against mastitis-causing bacteria in dairy cows is to quickly recruit large enough numbers of opsonizing molecules and mature neutrophils into milk such that intramammary pathogens are cleared before they multiply significantly and the inflammatory response gets out of control. Currently, this challenge is best facilitated when established mastitis control procedures are practiced on the farm, including proper hygiene, milking procedures, and regular administration of approved mastitis vaccines. However, mastitis is still a significant problem. New animal functional genomics research is beginning to allow scientists to solve the puzzle of mastitis susceptibility. Results of this type of research offer the hope of giant leaps toward a clear identification of molecular genetic variation and potential gene targets for therapies and immune manipulations that could significantly reduce the risk of clinical mastitis in traditionally susceptible cows.