The multitude of cells, signaling pathways, receptors, novel genetic recombination mechanisms and interactive pathways of receptor function and cell differentiation that constitute the vertebrate adaptive immune system are integrally linked with the multicomponent innate immune system. At first glance, the levels of complexity seen in both systems at the phylogenetic level of mammals present what seem to be insurmountable hurdles in terms of achieving a systematic understanding of the evolution of immunity. New research directions and approaches suggest that resolution of many long-standing questions in this area is now possible. Historically, immunologists considered lower vertebrates and invertebrates as “simpler” forms, i.e., they were expected to possess more basic (less layered) levels of immunological complexity and thus potentially would serve as important resources. By considering the systematic placement of representative species in the context of phylogeny, characterizing their immune receptors, co-receptors as well as accessory molecules and evaluating responses to immunologic stimuli, it was thought that a clearer picture of immune evolution would emerge. There is no doubt that this approach has achieved some notable successes but for the most part it has fallen short in terms of achieving a broad understanding of the immunologic needs of many relevant models and how adaptive change in immune function is effected. Even if a structurally relevant ortholog of an immune effector is identified in a model organism, there is no reason to assume that it functions in a corresponding manner in disparate phylogenetic taxa. For example, survival of a sessile marine invertebrate, whose anatomical form puts it in open and contiguous contact with a literal sea of microorganisms and viruses, would be thought to depend, at least in part, on a “capable” immune response; however, at present, we have no real understanding of how this is achieved in an integrated manner. Furthermore, questions arise as to whether or not phenomena that are considered integral components of vertebrate-type immunity such as memory, tolerance, somatic change and clonal selection exist in invertebrates and if their functions parallel those recognized in mammals. More often than not, our interpretations are guided by preconceived notions that are based on observations made in distant species that often do not apply to far- removed taxa. We anticipate that major advances in our understanding of this broad subject are now forthcoming as resources exist or are being developed for examining important model organisms in their natural environments instead of within the confines of in vitro systems of potentially remote physiological significance. Taking a wide range of hypotheses, observations and interpretations into account, in this special topic, contributors have developed a comprehensive overview emphasizing new directions and interpretations for understanding basic aspects of immunity that consider unique features inherent to various model systems, their life histories and habitats. Approaches applied with key model organisms maintained and confronted with relevant challenges under natural conditions are emphasized. Current concepts of self and nonself are addressed not only in terms of immunity but also reproductive fitness. How genetic variation in immune effector molecules is achieved and maintained in natural populations is examined; particular attention is directed to response interfaces that factor in symbiotic interactions. Gene expansion and mechanisms of genetic diversification are explored. How diverse molecules and a variety of effector cells contribute to our broad understanding of the evolution of a remarkably complex, integrated system and how this work is facilitating our understanding of mammalian immunity is addressed.