The goal of this work is to study human whole-body gas exchange and cerebral autoregulation using a mathematical model. Previously, a human cardiopulmonary (CP) model [45, 47] was developed, which included heart, closed-loop blood circulation, gas exchange at lungs and baroreflex control of arterial pressure. In the current study, two major extensions to the model are made. First, a description of gas exchange in the peripheral tissues is added and is coupled with the lung gas exchanger via the circulatory loop with variable transport delays. A peripheral chemosensitive loop is also added to mimic the influence of blood gas composition on the heart and vasculature. The CP model is then used to predict the integrated cardiovascular and blood-tissue gas transport responses to pronounced changes in lung gas composition, and thus simulates changes encountered in apnea with and without passive oxygenation. The second extension of the CP model includes a more detailed description of cerebral circulation, cerebrospinal fluid (CSF) dynamics, brain gas exchange and cerebral blood flow (CBF) autoregulation. Two CBF regulatory mechanisms are described: autoregulation and CO2 reactivity. Central chemoreceptor control of ventilation is also added. This new model is subsequently used to study cerebral hemodynamic and brain gas exchange responses to test protocols commonly used in the assessment of CBF autoregulation (e.g., carotid artery compression and the thigh cuff test). The model closely mimics the experimental findings and provides biophysically based insights into the dynamics and interactions of the associated physiological systems. In summary, this work represents a bold effort in large-scale modeling of physiological systems. The presented model accurately describes the physiological systems and can explain how the cardiovascular, pulmonary and autonomic nervous systems interact in response to a variety of cardiopulmonary challenges, such as apnea, carotid artery compression and the thigh cuff test. With further refinement, the model may help investigators to better understand the complex biophysics of cardiopulmonary diseases such as sleep-related disorders of breathing (obstructive and central sleep apnea) and complications associated with head-injuries.