Merocyanine 540-mediated photodynamic therapy (MC540-PDT) kills leukemia and selected solid tumor cells, enveloped viruses, virally infected cells, malaria parasites, parasitized red cells, and certain bacteria but is relatively well tolerated by normal pluripotent hematopoietic stem cells, granulocyte/macrophage progenitors, and mature red cells.  MC540 is not mutagenic and has a low systemic toxicity.  Unfortunately, MC540-PDT performs poorly under high-serum/plasma conditions because serum albumin and serum lipoproteins complete with cellular and viral binding sites for dye molecules, and it performs poorly under high-hemoglobin conditions because of spectral overlap with hemoglobin.  Furthermore, at physiological temperature, the dye is degraded in plasma/serum with a half-life of about 2 hours.  Recent investigations into structure-activity relationships have identified several analogues that are superior to MC540.  For example, replacing the oxygen in the donor heterocycle by sulfur or selenium renders the dye resistant to degradation by plasma/serum.  An expansion of the back ring from benzene to naphthalene significantly enhances cytotoxic and virucidal activity.  Replacing sulfur at the 2-position of the barbituric acid by selenium enhances singlet oxygen quantum yields by about 2 orders of magnitude and dramatically improves cytotoxic and virucidal activity.  All three beneficial modifications red-shift the absorption spectrum of the dye, thereby reducing spectral overlap with hemoglobin.   The photobleaching of selenobarbituric acid analogues generates colloidal selenium that combines with serum albumin and lipoproteins to form conjugates that are cytotoxic to leukemia and selected solid tumor cells but are well tolerated by normal hematopoietic stem cells.  Selenium-protein conjugates contribute substantially to the cytotoxic action of selenomerocyanine-PDT, especially if PDT is performed under high-serum/plasma conditions and at physiologic or near-physiologic temperature.  Photochemically generated selenium-protein conjugates represent a novel class of cytotoxic agents that may prove useful for the treatment of cancer.