The burden of newborn infectious disease has long been recognized as the highest across the entire human life span. The precise underlying cause is unfortunately still far from clear. A substantial body of data derived mostly from in vitro experimentation indicates "lower" host immune responses in early vs. adult life and is briefly summarized within this review. However, emerging data derived mostly from in vivo experimentation reveal that the newborn host also exhibits an exuberant immune and inflammatory response following infection when compared to the adult. In this context, it is important to emphasize that "infection" does not equate "infectious disease," as for many infections it is the host response to the infection that causes disease. This simple insight readily arranges existing evidence into cause-effect relationships that explain much of the increase in clinical suffering from infection in early life. We here briefly summarize the evidence in support of this paradigm and highlight the important implications it has for efforts to ameliorate the suffering and dying from infection in early life.