Substance P is known to be involved in respiratory rhythm and central pattern generating mechanisms, especially during early development. We therefore studied respiratory responses in transgenic newborn mice (Tac1 -/-), lacking substance P and neurokinin A (NKA). In vivo, the effects of intermittent isocapnic hypoxia (IH) and hypercapnia were studied, using whole-body flow plethysmography at P2-3 and P8-10. In vitro, anoxic responses and the effects of hypocapnic and hypercapnic conditions were studied in brainstem-spinal cord preparations (C4 activity) at P2. Hypoxic challenge considerably modified the respiratory activity in transgenic mice displayed in vivo as an attenuated increase in tidal volume during IH. Transgenic mice also showed a more prominent posthypoxic frequency decline in vivo and posthypoxic neuronal arrests appeared more often in vitro. We recognized two types of sigh activity, with or without a following pause. During IH, the amount of sighs with a pause decreased and those without increased, a redistribution that became stronger with age, only in controls. Intermittent anoxia induced long-term facilitation effects in controls, but not in Tac1 -/- animals, manifested as an increase in burst frequency in vitro and by an augmentation of ventilation during posthypoxic periods in vivo. Thus, our data demonstrate that a functional substance P/NKA system is of great importance for the generation of an adequate respiratory response to hypoxic provocation in newborn mice and during early maturation. It also indicates that substance P (and/or NKA) is involved in the development of the plasticity of the respiratory system.