All land vertebrates, including humans, use lungs to breathe air. The inspiratory and expiratory movements of the lungs are driven by a complex neural circuitry that consists of a central network in the brainstem that generates breathing rhythms and an output layer of motor neurons (MNs) which connect to respiratory muscles. These respiratory circuits develop prenatally and have to become functional immediately after birth. While significant progress has been made in understanding the central pattern generator itself, very little is known about the formation of neural circuits that turn breathing rhythms into coordinated motor output. Understanding the genetic program of respiratory MN differentiation is desirable for two reasons: First, respiratory MNs evolved after the basic vertebrate body plan was established and became more diverse during the evolution from ancestral tetrapods to mammals. Hence, understanding the logic of their genetic program might shed light on how neuronal developmental programs diversify, as organisms grow more complex. Second, in humans, loss of respiratory motor function is a leading cause of death in MN diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. Reconstitution of respiratory muscle innervation through cell replacement therapy is therefore of considerable medical interest and will require the generation of authentic respiratory MNs in vitro from embryonic stem cells or induced pluripotent cells. Elucidating how respiratory MN identity and connectivity is established during normal embryogenesis would greatly facilitate the development of such a therapeutic approach.