A tremendous amount of research has been conducted in recent years investigating the mechanisms of action by which the application of subatmospheric pressure to wounds increases the rate of healing. Similarly, numerous studies have also been conducted examining the physiologic response of wounds to the applied subatmospheric pressure. However, many more need to be conducted. A series of basic studies examining the use of subatmospheric pressure to treat wounds is presented, including the original studies upon which the vacuum-assisted closure device was based (on blood flow, granulation tissue formation, bacterial clearance, and survival of random-pattern pedicle flaps). Subsequent studies analyzing removed fluids, envenomation/extravasation, burns, grafts, and in vitro tissue culture studies are also reviewed. Two broad mechanisms of action are proposed: removal of fluid and mechanical deformation. Fluid removal both decreases edema--thus decreasing interstitial pressure and shortening distances of diffusion--and removes soluble factors that may affect the healing process (both positively and negatively). The relationship of mechanical deformation to increased growth is well known to plastic surgeons, as it is the basis of tissue expansion. While much has been done, a great deal more needs to be done to elucidate the mechanisms of action responsible for the dramatic response seen clinically.