The human (mammalian) immune response includes two interrelated but separable components: the innate immune system and an adaptive immune response. The former constitutes the sole immune defense strategy of invertebrates. It is only with vertebrate evolution that an adaptive immune response, first cellular, then later humoral, develops. Recent studies and a reconsideration of the innate system allow a fuller appreciation of its complexities, unique qualities, and irreplaceable value. In the early days of an infection, long before an effective adaptive immune response can be mounted, the innate system puts up an effective defense. Innate systems provide the costimulatory signal needed to unleash the adaptive immune response. Future contributions to this series will provide details about some of the specific innate immune systems. This article serves as an introduction to this underappreciated (until recently) aspect of human immune defenses.