Following the acquisition of multicellularity, organisms with increasing levels of specialized cells, tissues, and organs emerged during evolution. To coordinate specialized organs, long-distance interorgan communication systems appeared. The central nervous system evolved to regulate many organ behaviors, using hormones or neurons. In addition, organs developed systems to directly communicate their states to one another. This is illustrated by the lack of nervous systems in plants and simple animals like sponges, which can perform complex systemic functions (Lough and Lucas, 2006; Srivastava et al., 2010). Developmental or homeostatic events within cells or tissues have been extensively studied. For example, maintenance of the integrity of the Drosophila gut involves stem cell proliferation and differentiation, partially driven by local JAK/STAT, EGF, MAPK, and Wnt signaling (Panayidou and Apidianakis, 2013). Recently, it has become clear that individual organs themselves are also able to communicate their states. However, the nature of the interorgan signaling mechanisms remains largely a mystery.

Here, we review the emerging data supporting the existence of a vast interorgan communication network (ICN). The ICN is the network of peptides, proteins, and metabolites that act between organs to coordinate essential and specialized cellular processes under homeostasis and stress (Figure 1). We propose that studies in Drosophila, where, unlike in mammals, biochemical studies can be combined with genome-wide in vivo tissue-specific