The photodynamic therapy of tumors is based on a photosensitization reaction that produces oxygen-derived cytotoxic species. The availability of oxygen is therefore a necessary condition to obtain the desired effect. However, most tumors develop regions that have outgrown their vascular supply, and therefore present severe hypoxia. In many hypoxic, yet viable areas, oxygen partial pressures almost two orders of magnitude lower that in normal tissues have been measured by other authors. It is here suggested that hypoxic cells are resistant to the therapy and hence are a source of postirradiation recurrence of the tumors. Methods are reviewed and discussed that can be used to: (a) improve the tumor oxygenation status prior to, or during irradiation; (b) destroy hypoxic cells; and, (c) allow the reoxygenation of the tumor by using fractionated irradiation protocols which increase tumor photosensitivity. Hyperthermia, a therapy to which hypoxic cells are particularly sensitive, is discussed. Cellular and vascular parameters that should be considered when discussing the synergism between hyperthermia and photodynamic therapy are listed. The new research field of hypoxia mapping by nondestructive, noninvasive, imaging techniques is briefly discussed.