Photodynamic therapy (PDT) is now a reasonably well-known therapeutic option and is approved as a first line treatment of age-related macular degeneration (AMD), a non-oncologic condition. For most cancer applications PDT is approved mainly as a palliative or adjunctive treatment often when all other options have failed. As the modality evolves toward becoming a first-line or curative option, long-term effects of processes involved will need to be studied. Cellular and tissue responses to PDT are more complex than responses to the more conventional therapies, perhaps because PDT is inherently a binary (or ternary) therapy. In addition to the nature and localization of the photosensitizer (PS), the timing of illumination after administration, the mode of administration and the PS and light doses, the efficacy and selectivity of responses are also determined by the physiology and geometry of tumors, the inherent survivability of tumor cells (in circulation and other anatomic sites) and cellular and molecular responses to PDT. The overall outcome of photodynamic treatment in the long term is determined by a combination, in varying degrees, of all of the above factors. In order to enhance and broaden the application of PDT to complex anatomical sites, an understanding of these factors would be useful. In the laboratory, the outcome is also dependent on the specific animal models being studied. This manuscript discusses preliminary studies along these lines using a variety of tools and implications, if any, of the results obtained.