Cattle, like other vertebrates, are born into a world of microbes. Microbes, including commensals and potential pathogens that inhabit the compartments of the body, comprise what is now known collectively as the microbiome. The microbiome, along with the immune system, plays an important role in the health of all animals. To defend against pathogens, cattle and other vertebrates have multiple layers of defense that include three key components: physical barriers, innate immunity, and adaptive immunity. The lymphoid system is an integrated system composed of primary lymphoid organs such as the thymus and bone marrow. These are the sites where T and B cells develop and mature and become immunocompetent. In contrast, secondary lymphoid organs, such as lymph nodes and spleen, are where these cells encounter antigens and initiate immune responses. These immune system components function to block or react to pathogens, produce responses to bodily trauma, and preserve an animal’s health in a world full of challenges.