Breathing while submerged and exposed to increased ambient pressure imposes significant challenges on human physiology. Immersion-related redistribution of blood from the extremities leads to engorgement of the central veins and pulmonary vessels, raising right-sided intravascular pressures and reducing lung compliance. Cold, exercise, and negative pressure breathing may augment pulmonary arterial pressure and lead to fluid leakage from the bloodstream into the alveoli in susceptible individuals. Higher gas density and the associated increase in airways resistance, the breathing apparatus, and negative pressure breathing add resistive loads, resulting in a reduced maximum breathing capacity at depth. Hypercarbia, hyperoxia, and increased nitrogen dissolution in tissues may all potentially be hazardous and can impair consciousness, with a high risk of drowning underwater. On ascent from depth, dissolved nitrogen may form gas bubbles if tissues get supersaturated, and excess venous bubble load or gas passage through cardiac or intrapulmonary shunts may result in arterial gas embolism. Rapid reductions in pressure during ascent from depth may lead to pulmonary barotrauma due to overdistension of airspaces when trapped air expands. This article reviews the physics and the pertinent human physiology and pathophysiology associated with breathing or breath-holding at depth that are critical to understanding each of the problems noted above.