The limited penetration of laser radiation into biological tissue prevents the widespread distribution of photodiagnostics (PD) and photodynamic therapy (PDT) methods to clinical practice. We have investigated several approaches for PD and PDT of deep-seated tumors: 1. Stereotactic biopsy cannula with a laser spectroscopic control. Special fiber ports for long-term installation in the tumor removal area were developed in order to cause tumor cells to migrate not into the depth of brain but along the fibers with occasional laser irradiation for PD and PDT. The fibers are coated with a special compound containing photosensitizer (PS) and nutrients for cancer cells. 2. Neurosurgical aspirator with the function of video-fluorescence and spectroscopic analysis system. More than 500 patients with various types of brain tumors were operated on using fluorescent navigation based on 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (Pp IX) fluorescence under laser excitation in red spectral range. 3. Diagnostics and navigation of tumors when fluorescence is excited in the red and near infrared ranges. We used indocyanine green (ICG) as near infrared dye to observe blood and lymph vasculature of laboratory animals. This method could be useful while examining tumor bed and adjacent area. 4. Joint action of radiopharmaceuticals and PS based on Cherenkov radiation. Cell death by PDT mechanism via Pp IX excitation by Cherenkov radiation in mitochondria during 18F-fludeoxyglucose decay. This idea achieved good results on rats with C6 glioma. The results of using this approach with chlorin e6 PS in comparable doses are negative. 5. Action through photodynamic inactivation of tumor-associated macrophages and microglia. Idea of minimally invasive method for determining macrophage (microglia) phenotype and their polarization in tumors and their immediate vicinity in situ. This would allow evaluating the effectiveness of the treatment, including PDT. The most promising results were obtained with Pp IX and aluminum phthalocyanine nanoparticles. Studies have been conducted on experimental animals with grafted tumors and, in part, on cancer patients in the clinic.