INTRODUCTION: Chemotherapy is a primary treatment option in human and veterinary oncology. Like humans, canine patients often develop drug resistance. Comparative oncology is gaining increasing interest, and spontaneous tumors of companion dogs have emerged as a powerful resource for better understanding human cancer. The genetic, molecular, and histological features of tumors in dogs are more closely related to those in humans than the ones in laboratory animals, including complex mechanisms of drug resistance. METHODS: A comprehensive literature search was conducted in the electronic database Clarivate Web of Science (WOS): Medical Literature Analysis and Retrieval System Online (MEDLINE) from 1990 to 2025 (updated 22 January 2025). The final set includes 59 relevant full-text English articles. RESULTS: The literature findings suggest that canine spontaneous tumors are valuable model systems with important translational implications for identifying novel mechanisms of chemotherapy resistance shared with humans and may help advance the current standard of care in precision medicine. CONCLUSIONS: We have provided an updated overview of the role of canine tumor models to study oncotherapy resistance, focusing on limitations and opportunities for advancement. Despite complementary benefits of such models in translational oncology research, their relevance remains underestimated. Strengthening the collaboration between human and veterinary medicine professionals and comparative medicine researchers, and obtaining the support of interdisciplinary institutions, could contribute to addressing the problem of multidrug resistance for both human and canine patients. Future research may promote using canine spontaneous tumors as translational therapeutic models for human chemoresistance, through a multidisciplinary approach based on the emerging "One Health, One Medicine" paradigm.