Nutrition profoundly shapes immunity and inflammation across the lifespan of mammals, from pre- and post-natal periods to later life. Emerging insights into diet-microbiota interactions indicate that nutrition has a dominant influence on the composition-and metabolic output-of the intestinal microbiota, which in turn has major consequences for host immunity and inflammation. Here, we discuss recent findings that support the concept that dietary effects on microbiota-derived metabolites potently alter immune responses in health and disease. We discuss how specific dietary components and metabolites can be either pro-inflammatory or anti-inflammatory in a context- and tissue-dependent manner during infection, chronic inflammation, and cancer. Together, these studies emphasize the influence of diet-microbiota crosstalk on immune regulation that will have a significant impact on precision nutrition approaches and therapeutic interventions for managing inflammation, infection, and cancer immunotherapy.