Spontaneous breathing is characterized by a complex pattern of inspiratory muscle activation. The primary source of inspiratory drive to the diaphragm and intercostal muscles arises from bulbospinal projections to spinal interneurons and motoneurons1,2. In contrast to the conventional view that motor control of inspiratory muscle activation resides largely in upper respiratory centers, several studies indicate that important control mechanisms also exist at a spinal level. Specific reflexes, mediated by spinal interneurons, provide separate auto control of diaphragm and intercostal muscle activation while other reflexes affect the interplay between the different major inspiratory muscles and coordination of their actions. For example, diaphragm activation is modulated by excitatory and inhibitory phrenic to phrenic reflexes and intercostal to phrenic reflexes while inspiratory intercostal activation is modulated by intercostal to intercostal and phrenic to intercostal reflex effects. While some reflex effects are clearly spinal in origin, there are likely supraspinal inputs, as well. Differentiating the source of some of these individual reflex effects has been difficult to discern. New models of inspiratory muscle activation via electrical stimulation techniques however may shed some light on this issue. Recent studies in an animal model of spinal cord injury (C2 preparation) have shown that the phrenic and inspiratory intercostal motoneuron pools can be activated via low intensity, high frequency spinal cord stimulation (HF-SCS) at the T2 level in a remarkably physiological manner8-11. The diaphragm and inspiratory intercostal muscles are activated asynchronously as in normal breathing and the firing frequencies of these muscles are nearly identical to that occurring during spontaneous breathing. Since participation of the upper respiratory centers has been eliminated, this preparation provides a useful model to separately assess the influence of spinal mechanisms on inspiratory muscle activation. During spontaneous breathing in both animals and humans, there is greater activation of both the parasternal and external intercostal muscles in the upper interspaces and greater activation of the dorsal compared to ventral fibers within a given interspace. Interestingly, this pattern is a highly efficient one as it also matches the mechanical advantage of these individual muscles between interspaces and also muscles fibers within a given interspace. During HF-SCS following C-2 section in dogs, this same pattern has been observed for both the parasternal and external intercostal muscles, in separate trials. These results indicate that the specific complex pattern of intercostal muscle activation does not depend upon input from supraspinal centers but resides at the level of the spinal cord. While there are number of possible mechanisms operative at a spinal cord level which could mediate differential intercostal activation, these results fit the hypothesis that there is an important role of spinal interneurons in the control of inspiratory muscle activation. In this same preparation, the relative participation of the diaphragm and intercostal muscles during HF-SCS can also be reflexly modulated. Unilateral phrenic nerve section results in an increased activity of the ipsilateral, but not the contralateral, inspiratory intercostal muscles. Previous animal studies, which demonstrate bilateral inhibitory effects in response to phrenic nerve section, may involve supraspinal mechanisms. In addition, the external intercostal muscles demonstrate significant post-inspiratory activity during HF-SCS. These results support previous hypotheses, that reflex effects from muscle spindle afferents are the primary cause of post-inspiratory activity, rather than input from higher centers. In conclusion, the precise role of the spinal cord neural network in the control of breathing may have been underestimated and with the proper tools, the importance of spinal mechanisms can be further elucidated.