Many factors, including stress, contribute to the increased risk for disease during certain periods of life in dairy cattle, and factors that contribute to disease vary dramatically between herds. The immune system of cattle may become dysfunctional and increase the likelihood of infectious diseases, many of which are caused by environmental microorganisms. The stress response is essential for the physiological adaptation to change; however, prolonged stress or a maladaptation is in the etiology of immune dysfunction and increased disease. Stress affects the immune system of animals both through direct and indirect mechanisms. Direct impacts are mediated through catecholamine and glucocorticoid pathways, whereas indirect mechanisms are largely directed through altered digestive and metabolic functions. A few examples of indirect mechanisms that were presented include (1) dietary changes, either during weaning or the transition period, alters microbial ecology and/or increases total gastrointestinal permeability, (2) excessive lipolysis during early lactation causes macrophage infiltration into adipose tissue that further exacerbates the negative effects of body condition loss, (3) maladaptation of the homeorhetic calcium system can impair leukocyte function and increase the risk for disease, and (4) long-term, even trans-generational, consequences of disease sequelae on reproduction. Inflammation was discussed in many contexts, both positive and negative. Inflammation is an essential adaptation mechanism, but also contributes to pathological disruption of normal tissue function. An activated immune response, initiated through an inflammatory response, is metabolically expensive and diverts nutrients and energy away from milk synthesis and reproduction toward immune defense and tissue repair. Further, the severity of an infectious disease in many cases is directly related to the degree of inflammation in a tissue. Improved ability of animals to adapt to physiological changes, tolerance to pathogens, early diagnosis, and quick interventions were discussed as key strategies to improve health and limit the negative impacts of disease.