Objective: This study aimed to investigate the feasibility and predictive value in performing ex vivo drug sensitivity testing on bone sarcomas from patients with refractory disease and identify agents with potential therapeutic benefit. Methods: A cohort of 7 osteosarcomas (OS) and 4 Ewing sarcoma (ES) patient-derived cells (PDCs) were screened against a library of oncological drugs, gene panel sequencing and mRNA expression arrays. Drug responses were correlated to the molecular characteristics of specific sarcoma subtypes and patient response to therapy. Results: OS PDCs showed heterogeneous drug sensitivity, with observed responses for mTOR, PKC, MAPK and CDK inhibitors that correlated with the histological subtype and genotype of the primary tumor. Two of 4 ES PDCs displayed morphological dichotomy as separate Ews-Fli1 positive spheroid and adherent populations. These ES PDCs showed comparable responses to most of the oncological drugs but differential sensitivity to rapalogs and SMAC-mimetics. In both, OS and ES, the drug sensitivity of PDCs correlated to the patient response to chemotherapy. Conclusion: Drug sensitivity testing of PDCs from bone sarcomas is a valuable tool for a rapid identification of potential treatments, in otherwise genetically complex group of tumors where genome-based assays are difficult to implement. Clones with different phenotypes can outgrow in PDC cultures and can represent clonal evolution that give raise to tumor recurrence.