More than a century has passed since the beginning of direct experimentation on control of ventilation, and the ensuing years have brought considerable insight into the mechanisms of this control. Much of what we know about cellular chemosensitivity in mammals comes from a limited number of species; yet, given the diversity of circumstances in which mammals exist, their potential has been greatly underused. Here we review some of the environmental situations for plasticity of mammalian central chemosensitivity and function of chemosensors. “Normal” breathing patterns change during sleep, hibernation, and exercise, and central chemosensitivity must be altered during acclimation or adaptation to altitude, burrowing, or disease states. Where central chemosensitive cells are located, and what qualifies a cell as chemosensitive, is currently debated. The chemosensitivity of these cells changes over development, and the signaling mechanisms of these cells vary between chemosensitive regions, probably accounting for plasticity in response to environmental perturbations.