The significance of neuroplasticity in respiratory motor control has been appreciated only in recent years (Mitchell and Johnson, 2003). One important model of respiratory plasticity, known as respiratory long-term facilitation (LTF), is induced by acute intermittent hypoxia (AIH). LTF is expressed as a progressive increase in respiratory motor output lasting several hours after the final hypoxic episode. LTF is expressed differentially in nerves innervating respiratory pump muscles (eg. phrenic) versus upper airway muscles that regulate airway resistance and patency (eg. XII). LTF exhibits metaplasticity since pretreatment with chronic intermittent hypoxia enhances AIH-induced LTF. Although the functional significance of LTF remains uncertain, it has been proposed to stabilize breathing during sleep (Mahamed and Mitchell, 2007). Regardless of its specific physiological role, our perspective is that the capacity to elicit LTF may be harnessed as a therapeutic approach to multiple clinical disorders of ventilatory control. Thus, a detailed understanding of cellular mechanisms giving rise to LTF may provide the rationale for new pharmacological approaches in the treatment of ventilatory control disorders, such as obstructive sleep apnea or respiratory insufficiency following spinal cord injury or during motor neuron disease. Cellular/synaptic mechanisms of LTF have been studied most frequently in phrenic motor output. Phrenic LTF (pLTF) requires spinal serotonin activation and protein synthesis (Baker and Mitchell, 2002). Our working model is that intermittent hypoxia triggers intermittent serotonin release in the phrenic motor nucleus, initiating pLTF via 5-HT2 receptor activation on respiratory motor neurons. Serotonin receptor activation initiates signaling cascades, leading to new protein synthesis and pLTF maintenance. A critical protein in pLTF expression is brain-derived neurotrophic factor (BDNF; Baker-Herman et al., 2004). New BDNF synthesis is necessary for pLTF since intrathecal siRNAs targeting BDNF mRNA abolish new BDNF synthesis and pLTF. By activating the high affinity BDNF receptor, TrkB, ERK MAP kinases are phosphorylated and activated, leading to pLTF. Although less is known concerning mechanisms downstream from ERK activation, we propose that glutamate receptor trafficking is induced, increasing synaptic strength between (glutamatergic) brainstem respiratory neurons and phrenic motor neurons. pLTF expression is actively regulated. For example, serine/threonine phosphatases (PP2A/5) constrain pLTF. During AIH, NADPH oxidase activity is increased, increasing the formation of reactive oxygen species which subsequently inhibit relevant phosphatases and relieve the phosphatase constraint to pLTF (MacFarlane et al., 2008). Considerable progress is being made in understanding fundamental mechanisms of LTF, and we are beginning to the potential to harness this mechanism in an attempt to treat respiratory control disorders. Promising approaches include selective administration of repetitive acute intermittent hypoxia to induce respiratory plasticity without pathological consequences and small molecules that cross the blood brain barrier and simulate the actions of BDNF, such as Gs protein coupled receptor agonists (Golder et al., 2008). Although research on respiratory plasticity is still in its infancy, progress has been rapid, and there is considerable promise that it will lead to novel and effective therapeutic approaches to the treatment of devastating disorders in respiratory control for which there are no known cures.