www.frontiersin.org Macroevolutionary Immunology: A Role for Immunity in the Diversification of Animal life An emerging picture of the nature of immune systems across animal phyla reveals both conservatism of some features and the appearance among and within phyla of novel, lineage-specific defense solutions. The latter collectively represent a major and underappreciated form of animal diversity. Factors influencing this macroevolutionary (above the species level) pattern of novelty are considered and include adoption of different life styles, life histories, and body plans; a general advantage of being distinctive with respect to immune defenses; and the responses required to cope with parasites, many of which afflict hosts in a lineage-specific manner. This large-scale pattern of novelty implies that immunological phenomena can affect microevolutionary processes (at the population level within species) that can eventually lead to macroevolutionary events such as speciation, radiations, or extinctions. Immunologically based phenomena play a role in favoring intraspecific diversification, specialization and host specificity of parasites, and mechanisms are discussed whereby this could lead to parasite speciation. Host switching – the acquisition of new host species by parasites – is a major mechanism that drives parasite diversity and is frequently involved in disease emergence. It is also one that can be favored by reductions in immune competence of new hosts. Mechanisms involving immune phenomena favoring intraspecific diversification and speciation of host species are also discussed. A macroevolutionary perspective on immunology is invaluable in today’s world, including the need to study a broader range of species with distinctive immune systems. Many of these species are faced with extinction, another macroevolutionary process influenced by immune phenomena. Recent years have witnessed a dramatic increase in our understanding of the diversity of immune systems across animal phyla (Flajnik and Kasahara, 2010; Messier-Solek et al., 2010; Rast and Litman, 2010; this volume) . Availability of genome sequences from a broad variety of animals coupled with an increased appreciation for the diversity of their defenses has given the study of immunity a much stronger evolutionary foundation, one that has been further enriched by studies of plant immunity and responses of bacteria and archaea to threats to their genomes (Horvath and Barrangou, 2010) . The increasing depth and breadth of immunological studies is also bringing to light a greater awareness of the impact that immunity has had on all forms of life, especially parasites. Here "parasite" is used inclusively, referring to infectious agents ranging from viruses to bacteria to protists to multicellular helminths. The features uniting parasites are that they infect hosts, provoke some degree of fitness-diminishing harm, prompt the deployment of immune responses, and undertake immune evasive actions. "Immune systems" are referred to as those molecules, cells, tissues, and organs that protect hosts from parasites (see caveats below). This discussion excludes a broad range of behavioral defenses like preening (Bush and Clayton, 2006) or avoidance (e.g., Mooring et al., 2003; Garnick et al., 2010) .