Eupneic breathing of mammals is not simply an alternation between inspiratory lung inflation and expiratory lung deflation as a passive relapse of the lungs. Normal quiet breathing in vivo involves a precisely co-ordinated interplay between inspiratory and post-inspiratory muscle contractions, variable but rare expiratory muscle contractions, and a concomitant adjustment of sympathetic cardiovascular and vagal cardiac activities, all together being organized by a common cardio-respiratory control system. As we do not only breathe quietly but possibly also want to dine, sing and dance, for example, such in vivo control cannot just rely upon autonomous pacemaker cells rigidly driving a ventilator pump, but requires in a highly dynamic plasticity of neural network control. To increase the options for such varying behavioural phenotypes, mammals have developed quite a complex network involving diverse assemblies of distinct classes of respiratory neurones localized in the ventral region of the brainstem that extends in a rostro-caudal direction from the pons to the cervical spinal cord. A commanding “kernel”, however, is localized in the pre-Bötzinger Complex (pre-BötC) just caudal to the compact division of the nucleus ambiguus. Its vital role was demonstrated by the finding that in vivo rhythmic respiratory output from the brainstem disappears when the pre-BötC is lesioned. Such findings allowed the isolatation of a spontaneously active respiratory network in “reduced” preparations, such as the “en bloc” brainstem-spinal cord preparation or the ‘rhythmic’ brainstem slice of neonatal rat or mouse containing the pre-BötC. These preparations endogenously generate a “respiratory-like” rhythmic activity. The activity pattern is, however, quite different to the normal (eupneic) pattern as seen in more intact preparations like the in situ network in the arterially perfused working heart-brainstem preparation of rat and mouse or the fully intact in vivo preparations of anaesthetized mini-pig, cat, rat or mouse. A clear distinction between the “quality” of the various preparations can be drawn by the capacity of the network in the preparation to alter inspiratory and post-inspiratory activity patterns and oscillatory frequency to changes in behaviour or metabolic demands as well as their ability to demonstrate dynamic plasticity in response to modulating influences. The lecture will start with the cellular biophysics and continue with various aspects of synaptic interaction and integration to explain how under in vivo conditions potential pacemakers are kept under harsh control. It will then address the repertoire of metabotropic receptors acting through separate and convergent signal pathways onto ionotropic receptors and describe the molecular and cellular processes underlying a vital network plasticity that includes unexpected changes in network configuration to maintain rhythmicity. The final aspect will deal with translational approaches to pharmacotherapies treating life-threatening disturbances of network functions.