Immune systems are, increasingly, being studied from comparative perspectives. The analysis of the immunedefense systems of invertebrates, such as fruit flies and earthworms, is an important part of this effort. These systems are innate, natural non-specific, non-anticipatory and non-clonal. This is in contrast to the macrophage T and B systems that characterize vertebrate adaptive immunity whose properties can be categorized as adaptive, induced, specific, anticipatory, and clonal. In this review, we will focus on the earthworm system. Earthworms, like other complex invertebrates, possess several leukocyte types and synthesize and secrete a variety of immunoprotective molecules. The system as a whole effects phagocytosis, encapsulation, agglutination, opsonization, clotting and lysis of foreign components. At least two major leukocytes, small coelomocytes, and large coelomocytes mediate lytic reactions against several targets. Destruction of tumor cells in vitro shows that phagocytosis and natural killer cell responses are distinct properties of coelomocytes. A third type, the chlorogogen cell, synthesizes and sheds effector lytic molecules. Among the lytic molecules, three have been identified and sequenced (fetidins, CCF-1, lysenin) and another has been discovered (eiseniapore), while three other molecules, H1 H2 H3, share agglutinating and lysing functions. In contrast to these, Lumbricin I is the only known molecule of the earthworm system that is antimicrobial but non-lytic. Altogether the cellular and humoral components of the earthworm system function to distinguish between self and not self, dispose of internal (cancer?), damaged components and external antigens (microbes). The evolutionary context of the earthworm innate immune system is discussed at the end of this article. BioEssays 24:319–333, 2002. ©2002 Wiley Periodicals, Inc.