Sarcomas arise in patients of all ages and account for approximately 1% of new cancer diagnoses in Norway and the United States. Osteosarcoma is a subtype of sarcoma that typically affects children and adolescents and accounts for 8.9% of cancer-related deaths in children worldwide. Even though osteosarcoma is relatively rare, the low 5-year survival rate of 60-70% and the occurrence in children is the reason why novel approaches are necessary for this aggressive disease. Surgery and chemotherapy are the two main treatments for patients and ionizing radiation is included as an adjuvant with the attempt to control local recurrence as well as metastases, which is the major cause of mortality. Osteosarcomas frequently exhibit numerous mutations and aneuploidies which contribute to the aggression of the disease. Intrinsic or treatment-acquired resistance to chemotherapy and ionizing radiation is common in osteosarcoma patients and this contributes to the pressing need of developing novel therapeutic approaches for this disease. The present project evaluated photochemical internalization (PCI), a method for intracellular drug delivery, as an approach to osteosarcoma treatment. The project included patient derived osteosarcoma cell lines, OSA and MG-63, which were subjected to numerous rounds of chemotherapy and radiation in order to generate resistant forms. Ionizing radiation-resistant cell lines, OSA/IR and MG-63/IR, were generated by biweekly exposure of 7.5 Gy for 2.5 weeks and 5 Gy for 2 weeks, respectively. One doxorubicin-resistant cell line, MG-63/DR, was established by continuous exposure to 0.5 µM doxorubicin for 3 weeks. MG-63/IR and MG-63/DR were both found moderately resistant to ionizing radiation and doxorubicin, respectively, when compared to the parental cells. No ionizing radiation-resistance was, however, obtained in the OSA/IR cell line. RNA sequencing was applied to the nontreated parental cells as well as the resistant cells. The sequencing data was assessed to evaluate mechanisms of resistance as well as possible targets for therapy to be used alongside PCI. Overall, the RNA sequencing indicated the resistant cell lines to be more aggressive compared to the parental cell lines. Western blotting confirmed that both parental cell lines highly expressed the epidermal growth factor receptor (EGFR). An EGFR-targeted toxin, EGF/rGel/rGel, was therefore tested on the cell lines in combination with PCI. A strong treatment response of PCI-EGF/rGel/rGel was observed in all parental and resistant cell lines, in contrast to PCI-rGel, indicating PCI-EGF/rGel/rGel as a promising treatment approach for EGFR expressing, treatment resistant osteosarcoma.